Embryology - User contributions [en-gb]

User:Z3289066

2011-10-24T22:05:14Z

Z3289066:

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

--'''Elisabeth Karsten''' 11:05, 13 October 2011 (EST)

--'''Elisabeth Karsten''' 11:06, 20 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

A maternal infection of rubella during the second trimester has been known to cause deafness in the neonate.

''Identify 3 factors that contribute to poor neonatal drainage of the middle ear.''

Normally, the Eustachian tube aerates the middle ear and clear mucus from the inner ear into the nasopharynx. The neonatal Eustachian tube is not yet fully developed, and so can have reduced middle ear drainage.

1. The tube is quite short

2. It is angled horizonally, and so drainage is not entirely effective

3. In adults two muscle are active in keeping the tube open, in neonates only one is active

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg WS1 - OMIM]

==Lab Eleven==

''Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.''

Interatrial septation is formed from the fusion of two muscular septum (primum and secondum). During gestation, blood is able to pass from the right atria to the left via a shunt. This shunt or passage is known as the '''foramen ovale'''.

''Identify the cardiac defects that arise through abnormal development of the outflow tract.''

*Truncus arteriosus - where only one artery arise from the heart to form the pulmonary arteries and the aorta

*Conus arteriosus - where only one artery arise from the heart to form the pulmonary arteries and the aorta

*Tetralogy of Fallot

*Transposition of the Great Vessels

*Hypoplastic Left Heart

*Left Ventricular Outflow Tract Obstruction

*Right Ventricular Outflow Tract Obstruction

==Lab Twelve==

''Give examples of 3 systems that continue to develop postnatally.''

*Respiratory system

*Musculoskeletal

*Genital

''Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM.''

*Phenylketonuria (PKU)

*Biotinidase Deficiency

*Congenital Adrenal Hyperplasia (CAH)

*Congenital Hypothyroidism (CH)

*Congenital Toxoplasmosis

*Cystic Fibrosis (CF) - [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=219700 OMIM]

*Galactosemia (GAL)

*Homocystinuria

*Maple Syrup Urine Disease (MSUD)

*Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)

*Toxoplasma gondii IgM antibodies

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-24T22:03:33Z

Z3289066: /* Lab Twelve */

User:Z3289066

2011-10-20T00:26:16Z

Z3289066:

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

--'''Elisabeth Karsten''' 11:05, 13 October 2011 (EST)

--'''Elisabeth Karsten''' 11:06, 20 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

A maternal infection of rubella during the second trimester has been known to cause deafness in the neonate.

''Identify 3 factors that contribute to poor neonatal drainage of the middle ear.''

Normally, the Eustachian tube aerates the middle ear and clear mucus from the inner ear into the nasopharynx. The neonatal Eustachian tube is not yet fully developed, and so can have reduced middle ear drainage.

1. The tube is quite short

2. It is angled horizonally, and so drainage is not entirely effective

3. In adults two muscle are active in keeping the tube open, in neonates only one is active

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg WS1 - OMIM]

==Lab Eleven==

''Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.''

Interatrial septation is formed from the fusion of two muscular septum (primum and secondum). During gestation, blood is able to pass from the right atria to the left via a shunt. This shunt or passage is known as the '''foramen ovale'''.

''Identify the cardiac defects that arise through abnormal development of the outflow tract.''

*Truncus arteriosus - where only one artery arise from the heart to form the pulmonary arteries and the aorta

*Conus arteriosus - where only one artery arise from the heart to form the pulmonary arteries and the aorta

*Tetralogy of Fallot

*Transposition of the Great Vessels

*Hypoplastic Left Heart

*Left Ventricular Outflow Tract Obstruction

*Right Ventricular Outflow Tract Obstruction

==Lab Twelve==

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-20T00:06:39Z

Z3289066: /* Lab Attendance */

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

--'''Elisabeth Karsten''' 11:05, 13 October 2011 (EST)

--'''Elisabeth Karsten''' 11:06, 20 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

A maternal infection of rubella during the second trimester has been known to cause deafness in the neonate.

''Identify 3 factors that contribute to poor neonatal drainage of the middle ear.''

Normally, the Eustachian tube aerates the middle ear and clear mucus from the inner ear into the nasopharynx. The neonatal Eustachian tube is not yet fully developed, and so can have reduced middle ear drainage.

1. The tube is quite short

2. It is angled horizonally, and so drainage is not entirely effective

3. In adults two muscle are active in keeping the tube open, in neonates only one is active

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg WS1 - OMIM]

==Lab Eleven==

''Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.''

Interatrial septation is formed from the fusion of two muscular septum (primum and secondum). During gestation, blood is able to pass from the right atria to the left via a shunt. This shunt or passage is known as the '''foramen ovale'''.

''Identify the cardiac defects that arise through abnormal development of the outflow tract.''

*Truncus arteriosus - where only one artery arise from the heart to form the pulmonary arteries and the aorta

*Conus arteriosus - where only one artery arise from the heart to form the pulmonary arteries and the aorta

*Tetralogy of Fallot

*Transposition of the Great Vessels

*Hypoplastic Left Heart

*Left Ventricular Outflow Tract Obstruction

*Right Ventricular Outflow Tract Obstruction

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-17T01:01:35Z

Z3289066:

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

--'''Elisabeth Karsten''' 11:05, 13 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

A maternal infection of rubella during the second trimester has been known to cause deafness in the neonate.

''Identify 3 factors that contribute to poor neonatal drainage of the middle ear.''

Normally, the Eustachian tube aerates the middle ear and clear mucus from the inner ear into the nasopharynx. The neonatal Eustachian tube is not yet fully developed, and so can have reduced middle ear drainage.

1. The tube is quite short

2. It is angled horizonally, and so drainage is not entirely effective

3. In adults two muscle are active in keeping the tube open, in neonates only one is active

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg WS1 - OMIM]

==Lab Eleven==

''Name the components that give rise to the interatrial septum and the passages that connect the right and left atria.''

Interatrial septation is formed from the fusion of two muscular septum (primum and secondum). During gestation, blood is able to pass from the right atria to the left via a shunt. This shunt or passage is known as the '''foramen ovale'''.

''Identify the cardiac defects that arise through abnormal development of the outflow tract.''

*Truncus arteriosus - where only one artery arise from the heart to form the pulmonary arteries and the aorta

*Conus arteriosus - where only one artery arise from the heart to form the pulmonary arteries and the aorta

*Tetralogy of Fallot

*Transposition of the Great Vessels

*Hypoplastic Left Heart

*Left Ventricular Outflow Tract Obstruction

*Right Ventricular Outflow Tract Obstruction

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-13T00:05:29Z

Z3289066: /* Lab Attendance */

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

--'''Elisabeth Karsten''' 11:05, 13 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

A maternal infection of rubella during the second trimester has been known to cause deafness in the neonate.

''Identify 3 factors that contribute to poor neonatal drainage of the middle ear.''

Normally, the Eustachian tube aerates the middle ear and clear mucus from the inner ear into the nasopharynx. The neonatal Eustachian tube is not yet fully developed, and so can have reduced middle ear drainage.

1. The tube is quite short

2. It is angled horizonally, and so drainage is not entirely effective

3. In adults two muscle are active in keeping the tube open, in neonates only one is active

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg WS1 - OMIM]

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

2011 Group Project 3

2011-10-12T21:45:18Z

Z3289066:

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|260px|Figure 1: 47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="kline">Wikström AM, Dunkel L. '''Klinefelter syndrome'''. Best Pract Res Clin Endocrinol Metab: 2011, 25(2):239-50</ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in more detail below and portrayed in [[Media: 47,XXY Klinefelter's Syndrome.jpg|Figure 1]]. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="kline"/>

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]<ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="kline"/>

In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic [[#Glossary | '''nondisjunction''']] or [[#Glossary | '''anaphase lag''']]<ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|250px|Figure 3: The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|Figure 4: Risk factors associated with male breast cancer|thumb|250px|right]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. [[Media: Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|Figure 3]] is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with Klinefelter’s Syndrome compared to normal males. It has also been suggested that men with Klinefelter’s syndrome are 50% more at risk of being diagnosed with breast cancer, as shown in [[Media: Risk factors for male breast cancer.JPG|Figure 4]].<ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 500 male births<ref name="PMID17062147"/>, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals. Abnormal chromosome distribution, is the result of one of two mechanisms; [[#Glossary | '''non-disjunction''']] and anaphase lagging. However, Klinefelter’s syndrome is more commonly caused by [[#Glossary | '''non-disjunction''']].<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Non-Disjunction===

[[File:Maternal Non-Disjunction.PNG |thumb|right|500px|Figure 5:Maternal Non-disjunction.]]

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions, as shown in [[Media:Meiotic non-disjunction.jpg|Figure 5]]. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in [[Media: Maternal Non-Disjunction.PNG |Figure 5]]. However, the 47,XXY has been extensively studied and there is a 50-60% chance of it being from a paternal origin and 40-50% from a maternal origin<ref name="PMID11426451"><pubmed>11426451</pubmed></ref>. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. Studies have established that increased maternal age has adverse affects on pregnancy and an increased chance of anueploidy.<ref><pubmed>11582569</pubmed></ref> The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division <ref name="PMID12926525"/>.

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally.<ref name="PMID17415352"/> So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. In addition, it can also occur in both of the meiotic divisions, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in [[Media: Nondisjunction of Homologous Chromosomes in Meiosis1.jpg| Figure 7]], when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in [[Media: Nondisjunction of Sister Chromatids in Meiosis 2.jpg| Figure 8]]. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery caption="Images of Non-disjunction" widths="240px" heights="190px" align="center" perrow="3">

File:Meiotic non-disjunction.jpg |Figure 6: Meiotic Non-disjunction in Comparison with Normal Disjunction.

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg |Figure 7: Nondisjunction of Homologous Chromosomes in Meiosis 1.

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg |Figure 8: Nondisjunction of Homologous Chromosomes in Meiosis 2.
</gallery>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

==Pathophysiology==

Although extensive studies have been made to discover the pathophysiology of Klinefelter’s syndrome, i.e. the link between the supernumerary X and the phenotype, it remains largely unclear. However several genetic mechanisms may explain the variability of the phenotype, clinical features, life circumstances, life expectancy and fertility <ref name= "PMID20228051" />. Meiotic failure has essential roles in the parental origin of the X chromosome, gene-dosage effects in conjunction with possibly skewed X chromosome inactivation (XCI) and spermatogenesis<ref name= "PMID20228051"/><pubmed>20228051</pubmed></ref>. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"><pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

PAR1 comprises 2.6Mb of the short arm tips of both X and Y chromosomes, PAR2 at the tips of the long arms spans a much shorter region of 320kb. Since the sequencing of the X chromosome, it has been noted that PAR1 contains at least 24 genes whereas in PAR2 only 4 have been identified and that 10% of X chromosomal genes are specifically expressed in the testis<ref name= "PMID20228051"/>.

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*[[#Glossary | '''Cryptorchidism''']]
*Small penis
*[[#Glossary | '''Hypotonia''']]
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Figure 9. Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
*[[#Glossary | '''Gynecomastia''']] <ref name="PMID19221583"><pubmed>19221583</pubmed></ref>
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File:Pubertal_gynecomastia_1.jpg|thumb|center|Figure 10. Enlargement of the male breast, which is commonly seen in the pubertal period]]
|-
| '''Adulthood'''
|
*Mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
*Decreased [[#Glossary | '''Libido''']]
*High chance of being diagnosed psychiatric disorders, such as Schizophrenia, Bipolar disorder and Delusional disorder<ref name="PMID21655260"><pubmed>21655260</pubmed></ref>
*Less[[#Glossary | '''smooth pursuit eye movements''']]<ref name="PMID21655260"/>
*Lesser ability to adapt to stimulus<ref name="PMID21655260"/> As seen in figure 11 and 12, the height of the startle decreased as the nervous system has adapted to the [[#Glossary | '''prepulse''']]. However when comparing the two graphs, after a prepulse, the height of the startle experienced by the Klinefelter's syndrome group decreased by a lesser extent, when compared to the control group. This illustrates that Klinefelter's syndrome patient can not adapt to stimulus as well and thus will experience sensory overload and disjunctional cognition.
| [[File:Control group response to startle.jpg|thumb|center|Figure 11. EMG potentials in the control group of normal male subjects who respond to a startle (black line) and a startle after a prepulse (red line).]]
| [[File:Klinefelter syndrome group response to startle.jpg|thumb|center|Figure 12. EMG potentials in the Klinefelter's syndrome group who respond to a startle (black line) and a startle after a prepulse (red line).]]
|-
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb|300px]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Related Links==

'''Internal'''

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | This page describes the normal development of an oocyte, also discussing the abnormalities associated such as non-disjunction.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | This page, similarly, describes the normal development of the gametes and the associated abnormalities. The relate to the development of Klinefelter's syndrome.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | This page describes the process of meiosis and the possible associated irregularities such as non-disjunction.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | This page largely discusses the possible genetic abnormalities and their formation such as aneuploidy, which is the cause of Klinefelter's syndrome.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development] | Irregular genital development is one of the major symptoms associated with Klinefelter's syndrome. This page gives an overview of normal genital development and the associated abnormalities.

'''External'''

*[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | This page gives a concise summary of Klinefelter's syndrome.

*[http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet] | This is a detailed information booklet regarding Klinefelter's syndrome, published by the Australian Paediatric Endocrine Group

==Glossary==

*'''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

*'''Anaphase lag''' - Describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome

*'''Androgen''' - A male sex hormone, ie testosterone

*'''Aneuploidy''' - Abnormal number of chromosomes

*'''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Cryptorchidism''' - 1 or 2 testes have not dropped into the scrotum from the abdominal cavity

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''Hypotonia''' - reduced muscle tone

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Libido''' - sexual desire

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Prepulse''' - A weak stimulus that inhibits a reaction to the following stimulus.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Smooth pursuit eye movements''' - A slow and trailing eye movement which allows the moving object of attention to remain in line with the fovea.[http://www.ncbi.nlm.nih.gov/books/NBK10981/ Definition from the Neuroscience textbook]

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-12T21:41:59Z

Z3289066: /* Pathophysiology */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|260px|Figure 1: 47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="kline">Wikström AM, Dunkel L. '''Klinefelter syndrome'''. Best Pract Res Clin Endocrinol Metab: 2011, 25(2):239-50</ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in more detail below and portrayed in [[Media: 47,XXY Klinefelter's Syndrome.jpg|Figure 1]]. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="kline"/>

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]<ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="kline"/>

In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic [[#Glossary | '''nondisjunction''']] or [[#Glossary | '''anaphase lag''']]<ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|250px|Figure 3: The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|Figure 4: Risk factors associated with male breast cancer|thumb|250px|right]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. [[Media: Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|Figure 3]] is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with Klinefelter’s Syndrome compared to normal males. It has also been suggested that men with Klinefelter’s syndrome are 50% more at risk of being diagnosed with breast cancer, as shown in [[Media: Risk factors for male breast cancer.JPG|Figure 4]].<ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 500 male births<ref name="PMID17062147"/>, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals. Abnormal chromosome distribution, is the result of one of two mechanisms; [[#Glossary | '''non-disjunction''']] and anaphase lagging. However, Klinefelter’s syndrome is more commonly caused by [[#Glossary | '''non-disjunction''']].<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Non-Disjunction===

[[File:Maternal Non-Disjunction.PNG |thumb|right|500px|Figure 5:Maternal Non-disjunction.]]

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions, as shown in [[Media:Meiotic non-disjunction.jpg|Figure 5]]. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in [[Media: Maternal Non-Disjunction.PNG |Figure 5]]. However, the 47,XXY has been extensively studied and there is a 50-60% chance of it being from a paternal origin and 40-50% from a maternal origin<ref name="PMID11426451"><pubmed>11426451</pubmed></ref>. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. Studies have established that increased maternal age has adverse affects on pregnancy and an increased chance of anueploidy.<ref><pubmed>11582569</pubmed></ref> The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division <ref name="PMID12926525"/>.

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally.<ref name="PMID17415352"/> So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. In addition, it can also occur in both of the meiotic divisions, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in [[Media: Nondisjunction of Homologous Chromosomes in Meiosis1.jpg| Figure 7]], when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in [[Media: Nondisjunction of Sister Chromatids in Meiosis 2.jpg| Figure 8]]. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery caption="Images of Non-disjunction" widths="240px" heights="190px" align="center" perrow="3">

File:Meiotic non-disjunction.jpg |Figure 6: Meiotic Non-disjunction in Comparison with Normal Disjunction.

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg |Figure 7: Nondisjunction of Homologous Chromosomes in Meiosis 1.

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg |Figure 8: Nondisjunction of Homologous Chromosomes in Meiosis 2.
</gallery>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

==Pathophysiology==

Although extensive studies have been made to discover the pathophysiology of Klinefelter’s syndrome, i.e. the link between the supernumerary X and the phenotype, it remains largely unclear. However several genetic mechanisms may explain the variability of the phenotype, clinical features, life circumstances, life expectancy and fertility <ref name= "PMID20228051"><pubmed>20228051</pubmed></ref>. Meiotic failure has essential roles in the parental origin of the X chromosome, gene-dosage effects in conjunction with possibly skewed X chromosome inactivation (XCI) and spermatogenesis<ref name= "PMID20228051"/>. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

PAR1 comprises 2.6Mb of the short arm tips of both X and Y chromosomes, PAR2 at the tips of the long arms spans a much shorter region of 320kb. Since the sequencing of the X chromosome, it has been noted that PAR1 contains at least 24 genes whereas in PAR2 only 4 have been identified and that 10% of X chromosomal genes are specifically expressed in the testis<ref name= "PMID20228051"/>.

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*[[#Glossary | '''Cryptorchidism''']]
*Small penis
*[[#Glossary | '''Hypotonia''']]
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Figure 9. Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
*[[#Glossary | '''Gynecomastia''']] <ref name="PMID19221583"><pubmed>19221583</pubmed></ref>
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File:Pubertal_gynecomastia_1.jpg|thumb|center|Figure 10. Enlargement of the male breast, which is commonly seen in the pubertal period]]
|-
| '''Adulthood'''
|
*Mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
*Decreased [[#Glossary | '''Libido''']]
*High chance of being diagnosed psychiatric disorders, such as Schizophrenia, Bipolar disorder and Delusional disorder<ref name="PMID21655260"><pubmed>21655260</pubmed></ref>
*Less[[#Glossary | '''smooth pursuit eye movements''']]<ref name="PMID21655260"/>
*Lesser ability to adapt to stimulus<ref name="PMID21655260"/> As seen in figure 11 and 12, the height of the startle decreased as the nervous system has adapted to the [[#Glossary | '''prepulse''']]. However when comparing the two graphs, after a prepulse, the height of the startle experienced by the Klinefelter's syndrome group decreased by a lesser extent, when compared to the control group. This illustrates that Klinefelter's syndrome patient can not adapt to stimulus as well and thus will experience sensory overload and disjunctional cognition.
| [[File:Control group response to startle.jpg|thumb|center|Figure 11. EMG potentials in the control group of normal male subjects who respond to a startle (black line) and a startle after a prepulse (red line).]]
| [[File:Klinefelter syndrome group response to startle.jpg|thumb|center|Figure 12. EMG potentials in the Klinefelter's syndrome group who respond to a startle (black line) and a startle after a prepulse (red line).]]
|-
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb|300px]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Related Links==

'''Internal'''

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | This page describes the normal development of an oocyte, also discussing the abnormalities associated such as non-disjunction.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | This page, similarly, describes the normal development of the gametes and the associated abnormalities. The relate to the development of Klinefelter's syndrome.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | This page describes the process of meiosis and the possible associated irregularities such as non-disjunction.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | This page largely discusses the possible genetic abnormalities and their formation such as aneuploidy, which is the cause of Klinefelter's syndrome.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development] | Irregular genital development is one of the major symptoms associated with Klinefelter's syndrome. This page gives an overview of normal genital development and the associated abnormalities.

'''External'''

*[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | This page gives a concise summary of Klinefelter's syndrome.

*[http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet] | This is a detailed information booklet regarding Klinefelter's syndrome, published by the Australian Paediatric Endocrine Group

==Glossary==

*'''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

*'''Anaphase lag''' - Describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome

*'''Androgen''' - A male sex hormone, ie testosterone

*'''Aneuploidy''' - Abnormal number of chromosomes

*'''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Cryptorchidism''' - 1 or 2 testes have not dropped into the scrotum from the abdominal cavity

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''Hypotonia''' - reduced muscle tone

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Libido''' - sexual desire

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Prepulse''' - A weak stimulus that inhibits a reaction to the following stimulus.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Smooth pursuit eye movements''' - A slow and trailing eye movement which allows the moving object of attention to remain in line with the fovea.[http://www.ncbi.nlm.nih.gov/books/NBK10981/ Definition from the Neuroscience textbook]

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-12T21:40:11Z

Z3289066: /* Related Links */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|260px|Figure 1: 47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="kline">Wikström AM, Dunkel L. '''Klinefelter syndrome'''. Best Pract Res Clin Endocrinol Metab: 2011, 25(2):239-50</ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in more detail below and portrayed in [[Media: 47,XXY Klinefelter's Syndrome.jpg|Figure 1]]. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="kline"/>

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]<ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="kline"/>

In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic [[#Glossary | '''nondisjunction''']] or [[#Glossary | '''anaphase lag''']]<ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|250px|Figure 3: The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|Figure 4: Risk factors associated with male breast cancer|thumb|250px|right]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. [[Media: Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|Figure 3]] is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with Klinefelter’s Syndrome compared to normal males. It has also been suggested that men with Klinefelter’s syndrome are 50% more at risk of being diagnosed with breast cancer, as shown in [[Media: Risk factors for male breast cancer.JPG|Figure 4]].<ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 500 male births<ref name="PMID17062147"/>, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals. Abnormal chromosome distribution, is the result of one of two mechanisms; [[#Glossary | '''non-disjunction''']] and anaphase lagging. However, Klinefelter’s syndrome is more commonly caused by [[#Glossary | '''non-disjunction''']].<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Non-Disjunction===

[[File:Maternal Non-Disjunction.PNG |thumb|right|500px|Figure 5:Maternal Non-disjunction.]]

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions, as shown in [[Media:Meiotic non-disjunction.jpg|Figure 5]]. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in [[Media: Maternal Non-Disjunction.PNG |Figure 5]]. However, the 47,XXY has been extensively studied and there is a 50-60% chance of it being from a paternal origin and 40-50% from a maternal origin<ref name="PMID11426451"><pubmed>11426451</pubmed></ref>. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. Studies have established that increased maternal age has adverse affects on pregnancy and an increased chance of anueploidy.<ref><pubmed>11582569</pubmed></ref> The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division <ref name="PMID12926525"/>.

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally.<ref name="PMID17415352"/> So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. In addition, it can also occur in both of the meiotic divisions, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in [[Media: Nondisjunction of Homologous Chromosomes in Meiosis1.jpg| Figure 7]], when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in [[Media: Nondisjunction of Sister Chromatids in Meiosis 2.jpg| Figure 8]]. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery caption="Images of Non-disjunction" widths="240px" heights="190px" align="center" perrow="3">

File:Meiotic non-disjunction.jpg |Figure 6: Meiotic Non-disjunction in Comparison with Normal Disjunction.

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg |Figure 7: Nondisjunction of Homologous Chromosomes in Meiosis 1.

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg |Figure 8: Nondisjunction of Homologous Chromosomes in Meiosis 2.
</gallery>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

==Pathophysiology==

Although extensive studies have been made to discover the pathophysiology of Klinefelter’s syndrome, i.e. the link between the supernumerary X and the phenotype, it remains largely unclear. However several genetic mechanisms may explain the variability of the phenotype, clinical features, life circumstances, life expectancy and fertility <ref name= "PMID20228051" />. Meiotic failure has essential roles in the parental origin of the X chromosome, gene-dosage effects in conjunction with possibly skewed X chromosome inactivation (XCI) and spermatogenesis<ref name= "PMID20228051"/>. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

PAR1 comprises 2.6Mb of the short arm tips of both X and Y chromosomes, PAR2 at the tips of the long arms spans a much shorter region of 320kb. Since the sequencing of the X chromosome, it has been noted that PAR1 contains at least 24 genes whereas in PAR2 only 4 have been identified and that 10% of X chromosomal genes are specifically expressed in the testis<ref name= "PMID20228051"/>.

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*[[#Glossary | '''Cryptorchidism''']]
*Small penis
*[[#Glossary | '''Hypotonia''']]
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Figure 9. Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
*[[#Glossary | '''Gynecomastia''']] <ref name="PMID19221583"><pubmed>19221583</pubmed></ref>
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File:Pubertal_gynecomastia_1.jpg|thumb|center|Figure 10. Enlargement of the male breast, which is commonly seen in the pubertal period]]
|-
| '''Adulthood'''
|
*Mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
*Decreased [[#Glossary | '''Libido''']]
*High chance of being diagnosed psychiatric disorders, such as Schizophrenia, Bipolar disorder and Delusional disorder<ref name="PMID21655260"><pubmed>21655260</pubmed></ref>
*Less[[#Glossary | '''smooth pursuit eye movements''']]<ref name="PMID21655260"/>
*Lesser ability to adapt to stimulus<ref name="PMID21655260"/> As seen in figure 11 and 12, the height of the startle decreased as the nervous system has adapted to the [[#Glossary | '''prepulse''']]. However when comparing the two graphs, after a prepulse, the height of the startle experienced by the Klinefelter's syndrome group decreased by a lesser extent, when compared to the control group. This illustrates that Klinefelter's syndrome patient can not adapt to stimulus as well and thus will experience sensory overload and disjunctional cognition.
| [[File:Control group response to startle.jpg|thumb|center|Figure 11. EMG potentials in the control group of normal male subjects who respond to a startle (black line) and a startle after a prepulse (red line).]]
| [[File:Klinefelter syndrome group response to startle.jpg|thumb|center|Figure 12. EMG potentials in the Klinefelter's syndrome group who respond to a startle (black line) and a startle after a prepulse (red line).]]
|-
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb|300px]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Related Links==

'''Internal'''

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | This page describes the normal development of an oocyte, also discussing the abnormalities associated such as non-disjunction.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | This page, similarly, describes the normal development of the gametes and the associated abnormalities. The relate to the development of Klinefelter's syndrome.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | This page describes the process of meiosis and the possible associated irregularities such as non-disjunction.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | This page largely discusses the possible genetic abnormalities and their formation such as aneuploidy, which is the cause of Klinefelter's syndrome.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development] | Irregular genital development is one of the major symptoms associated with Klinefelter's syndrome. This page gives an overview of normal genital development and the associated abnormalities.

'''External'''

*[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | This page gives a concise summary of Klinefelter's syndrome.

*[http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet] | This is a detailed information booklet regarding Klinefelter's syndrome, published by the Australian Paediatric Endocrine Group

==Glossary==

*'''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

*'''Anaphase lag''' - Describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome

*'''Androgen''' - A male sex hormone, ie testosterone

*'''Aneuploidy''' - Abnormal number of chromosomes

*'''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Cryptorchidism''' - 1 or 2 testes have not dropped into the scrotum from the abdominal cavity

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''Hypotonia''' - reduced muscle tone

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Libido''' - sexual desire

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Prepulse''' - A weak stimulus that inhibits a reaction to the following stimulus.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Smooth pursuit eye movements''' - A slow and trailing eye movement which allows the moving object of attention to remain in line with the fovea.[http://www.ncbi.nlm.nih.gov/books/NBK10981/ Definition from the Neuroscience textbook]

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-12T21:39:15Z

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{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|260px|Figure 1: 47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="kline">Wikström AM, Dunkel L. '''Klinefelter syndrome'''. Best Pract Res Clin Endocrinol Metab: 2011, 25(2):239-50</ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in more detail below and portrayed in [[Media: 47,XXY Klinefelter's Syndrome.jpg|Figure 1]]. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="kline"/>

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]<ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="kline"/>

In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic [[#Glossary | '''nondisjunction''']] or [[#Glossary | '''anaphase lag''']]<ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|250px|Figure 3: The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|Figure 4: Risk factors associated with male breast cancer|thumb|250px|right]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. [[Media: Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|Figure 3]] is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with Klinefelter’s Syndrome compared to normal males. It has also been suggested that men with Klinefelter’s syndrome are 50% more at risk of being diagnosed with breast cancer, as shown in [[Media: Risk factors for male breast cancer.JPG|Figure 4]].<ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 500 male births<ref name="PMID17062147"/>, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals. Abnormal chromosome distribution, is the result of one of two mechanisms; [[#Glossary | '''non-disjunction''']] and anaphase lagging. However, Klinefelter’s syndrome is more commonly caused by [[#Glossary | '''non-disjunction''']].<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Non-Disjunction===

[[File:Maternal Non-Disjunction.PNG |thumb|right|500px|Figure 5:Maternal Non-disjunction.]]

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions, as shown in [[Media:Meiotic non-disjunction.jpg|Figure 5]]. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in [[Media: Maternal Non-Disjunction.PNG |Figure 5]]. However, the 47,XXY has been extensively studied and there is a 50-60% chance of it being from a paternal origin and 40-50% from a maternal origin<ref name="PMID11426451"><pubmed>11426451</pubmed></ref>. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. Studies have established that increased maternal age has adverse affects on pregnancy and an increased chance of anueploidy.<ref><pubmed>11582569</pubmed></ref> The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division <ref name="PMID12926525"/>.

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally.<ref name="PMID17415352"/> So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. In addition, it can also occur in both of the meiotic divisions, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in [[Media: Nondisjunction of Homologous Chromosomes in Meiosis1.jpg| Figure 7]], when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in [[Media: Nondisjunction of Sister Chromatids in Meiosis 2.jpg| Figure 8]]. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery caption="Images of Non-disjunction" widths="240px" heights="190px" align="center" perrow="3">

File:Meiotic non-disjunction.jpg |Figure 6: Meiotic Non-disjunction in Comparison with Normal Disjunction.

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg |Figure 7: Nondisjunction of Homologous Chromosomes in Meiosis 1.

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg |Figure 8: Nondisjunction of Homologous Chromosomes in Meiosis 2.
</gallery>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

==Pathophysiology==

Although extensive studies have been made to discover the pathophysiology of Klinefelter’s syndrome, i.e. the link between the supernumerary X and the phenotype, it remains largely unclear. However several genetic mechanisms may explain the variability of the phenotype, clinical features, life circumstances, life expectancy and fertility <ref name= "PMID20228051" />. Meiotic failure has essential roles in the parental origin of the X chromosome, gene-dosage effects in conjunction with possibly skewed X chromosome inactivation (XCI) and spermatogenesis<ref name= "PMID20228051"/>. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

PAR1 comprises 2.6Mb of the short arm tips of both X and Y chromosomes, PAR2 at the tips of the long arms spans a much shorter region of 320kb. Since the sequencing of the X chromosome, it has been noted that PAR1 contains at least 24 genes whereas in PAR2 only 4 have been identified and that 10% of X chromosomal genes are specifically expressed in the testis<ref name= "PMID20228051"/>.

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*[[#Glossary | '''Cryptorchidism''']]
*Small penis
*[[#Glossary | '''Hypotonia''']]
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Figure 9. Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
*[[#Glossary | '''Gynecomastia''']] <ref name="PMID19221583"><pubmed>19221583</pubmed></ref>
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File:Pubertal_gynecomastia_1.jpg|thumb|center|Figure 10. Enlargement of the male breast, which is commonly seen in the pubertal period]]
|-
| '''Adulthood'''
|
*Mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
*Decreased [[#Glossary | '''Libido''']]
*High chance of being diagnosed psychiatric disorders, such as Schizophrenia, Bipolar disorder and Delusional disorder<ref name="PMID21655260"><pubmed>21655260</pubmed></ref>
*Less[[#Glossary | '''smooth pursuit eye movements''']]<ref name="PMID21655260"/>
*Lesser ability to adapt to stimulus<ref name="PMID21655260"/> As seen in figure 11 and 12, the height of the startle decreased as the nervous system has adapted to the [[#Glossary | '''prepulse''']]. However when comparing the two graphs, after a prepulse, the height of the startle experienced by the Klinefelter's syndrome group decreased by a lesser extent, when compared to the control group. This illustrates that Klinefelter's syndrome patient can not adapt to stimulus as well and thus will experience sensory overload and disjunctional cognition.
| [[File:Control group response to startle.jpg|thumb|center|Figure 11. EMG potentials in the control group of normal male subjects who respond to a startle (black line) and a startle after a prepulse (red line).]]
| [[File:Klinefelter syndrome group response to startle.jpg|thumb|center|Figure 12. EMG potentials in the Klinefelter's syndrome group who respond to a startle (black line) and a startle after a prepulse (red line).]]
|-
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb|300px]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Related Links==

'''Internal'''

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | This page describes the normal development of an oocyte, also discussing the abnormalities associated such as non-disjunction.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | This page, similarly, describes the normal development of the gametes and the associated abnormalities. The relate to the development of Klinefelter's syndrome.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | This page describes the process of meiosis and the possible associated irregularities such as non-disjunction.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | This page largely discusses the possible genetic abnormalities and their formation such as aneuploidy, which is the cause of Klinefelter's syndrome.

*[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development] | Irregular genital development is one of the major symptoms associated with Klinefelter's syndrome. This page gives an overview of normal genital development and the associated abnormalities.

'''External'''

*[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | This page gives a concise summary of Klinefelter's syndrome.

*[http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet] | This is a detailed information booklet regarding Klinefelter's syndrome, published by the Australian Paediatric Endocrine Group

==Glossary==

*'''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

*'''Anaphase lag''' - Describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome

*'''Androgen''' - A male sex hormone, ie testosterone

*'''Aneuploidy''' - Abnormal number of chromosomes

*'''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Cryptorchidism''' - 1 or 2 testes have not dropped into the scrotum from the abdominal cavity

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''Hypotonia''' - reduced muscle tone

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Libido''' - sexual desire

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Prepulse''' - A weak stimulus that inhibits a reaction to the following stimulus.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Smooth pursuit eye movements''' - A slow and trailing eye movement which allows the moving object of attention to remain in line with the fovea.[http://www.ncbi.nlm.nih.gov/books/NBK10981/ Definition from the Neuroscience textbook]

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
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{{2011Projects}}

Talk:2011 Group Project 3

2011-10-10T10:03:49Z

Z3289066: /* Discussion */

[[2011_Group_Project_3|'''Group 3''']]: [[User:z3289066]] | [[User:z3289301]] | [[User:z3289829]] | [[User:z3289991]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_3_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_3_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Discussion==

I don't think the library has access to that paper :(. Personally I think we only need pathophysioloy section. But that's coming from someone doing a micro major. Is there enough informatin to do both?

--[[User:Z3289066|Elisabeth Karsten]] 21:03, 10 October 2011 (EST)

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Hey - just letting u guys no I will working on the signs and symptoms section today - I will try to fill it up with interesting things

--[[User:Z3289301|Dona Cho]] 13:54, 10 October 2011 (EST)

Hey guys!
I think that we should increase the size of the images - when I was looking through other sites I felt that readers should be able to read the images and not have increase it all the time. This way - by increasing the size of the images we will also be breaking up the chunks of text.

--[[User:Z3289301|Dona Cho]] 13:51, 10 October 2011 (EST)
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Hey guys, im sorry its taken me so long to get this done. Im going to re-write non-disjunction in aetiology (including Donna's part) and elaborate more on genetics (i will also fix up the images). But, do you guys think we should just write more in pathogenesis or start the new section pathophysiology?? Also, there's this article that i really want to read, but it seems to be locked, i would greatly appreciate it if someone could find an open version, its called "Klinefelter's syndrome: an analysis of the origin of the additional sex chromosome using molecular probes" by "JACOBS, P. A., HASSOLD, T. J., WHITTINGTON, E., BUTLER, G., COLLYER, S., KESTON, M. and LEE, M. (1988)

Thankyou. --[[User:Z3289829|Souti Khalil]] 00:41, 10 October 2011
(EST)

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Were we not planning to just replace pathogenesis with pathophysiology?

--[[User:Z3289066|Elisabeth Karsten]] 16:14, 9 October 2011 (EST)

Also guys, i was thinking that Pathophysiology should fall under the section on 'Pathogenesis'. What do you all think? My logic is that it will keep our webpage in a sequential order with aetiology, pathogenesis, pathophysiology etc...

I will add the section now and if you guys don't agree, you can always change it. --[[User:Z3289991|Robert Klein]] 11:31, 9 October 2011 (EST)

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Hey Souti,
I am quite happy with the changes. Might I suggest that under aetiology you change all the figure numbers, so for example, label the first figure in that row of figures under aetiology as figures 5-?--[[User:Z3289991|Robert Klein]] 11:28, 9 October 2011 (EST)

----

Hey guys, I just changed a few things in epidemiology, all I did was put the images to the right and number them figure 3 and 4. If you guys think it is best to go without figure 1, figure 2 ... then please feel free to change it.
I also changed;

“Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.
It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer [18] “

To

“Figure 3 is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with Klinefelter’s Syndrome compared to normal males. It has also been suggested that men with Klinefelter’s syndrome are 50% more at risk of being diagnosed with breast cancer, shown in Figure 4.”

Feel free to play around with what I’ve done. I personally prefer to number images, what do you guys think?
--[[User:Z3289829|Souti Khalil]] 23:00, 8 October 2011 (EST)

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Oh did he? I didn't realise. It can't hurt to change it. Ok no worries.

--[[User:Z3289066|Elisabeth Karsten]] 13:54, 7 October 2011 (EST)

Thanks a lot Liz! i'm currently at uni and i will be working on this tonight and during the weekend. Also, i noticed that you tweaked the links section, do you think Mark Hill will mind if we do it this way, as he did specify to have a section called 'Related Links'. --[[User:Z3289829|Souti Khalil]] 13:00, 7 October 2011 (EST)

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Pathophysiology -

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/21655260 This ones about the psychophysiology of having an additional X chromosome

http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1651-2227.2011.02246.x/pdf That's about the generally clinical features, with reference to pathology. It's got some good images, so I've requested permission for their use

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20014371 This one assess the differences of cognitive function of XXY and YYX patients - not sure it would be overly useful though

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20014369 Impact of XXY on cognitive function

I'll let you know if I find anything else

--[[User:Z3289066|Elisabeth Karsten]] 11:35, 7 October 2011 (EST)

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Haha, Dona can you see this?? Robert, Liz and I were talkingabout our group page and we thought that it may be better if we collate aetiology and pathogenesis, so there is no repetition. and then maybe add a pathophysiology section. I dont mind working on it. What do you think Dona?--[[User:Z3289829|Souti Khalil]] 12:10, 6 October 2011 (EST)

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Okay, so the page has undergone some reformatting. Hopefully this will look better, as Souti and Liz have been reorganising the content.--[[User:Z3289991|Robert Klein]] 11:30, 6 October 2011 (EST)

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Sounds good!! i will definately elaborate more in genetics and hopefull find an image to put there.
--[[User:Z3289829|Souti Khalil]] 10:25, 6 October 2011 (EST)

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I think that non-disjunction and genetics should be aetiology instead of pathogenesis. However Souti, you need to elaborate slightly more on the genetics.
--[[User:Z3289991|Robert Klein]] 10:23, 6 October 2011 (EST)

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Thanks Guys! The necessary changes to the Epidemiology have been made. See you all tomorow
--[[User:Z3289991|Robert Klein]] 15:55, 5 October 2011 (EST)

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Hey Liz, thanks, I think the history section is just about complete. I took into consideration all the peer reviews and changed a few things, however let me know if you think anything else needs to be done there. Epidemiology looks good rob!! Also, the picture in the introduction was just something that i found, but if you find a better image feel free to change it. I'll try to work on non-disjunction and aetiology later tonight. See you all tomorrow!

--[[User:Z3289829|Souti Khalil]] 13:49, 5 October 2011 (EST)

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That looks really good rob, nice work. The picture in the intro is nice, but it doesn't have a reference and we do already have an image of the Klinefelter karyotype in the Diagnosis section. I'll see if I can find something else for the intro. The timeline for history looks really good.

--[[User:Z3289066|Elisabeth Karsten]] 13:24, 5 October 2011 (EST)

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Hey Guys,
I tried to play around with an idea for epidemiology. Below is my idea. Note: I have changed nothing from Epidemiology on the main project page yet.

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]
One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.
A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.
Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.
[[File:Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png|thumb|left|Figure 3. The average intellect of boys with Klinefelter's Syndrome differs from that of normal males]]

--[[User:Z3289991|Robert Klein]] 13:40, 2 October 2011 (EST)

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I have amended the mistake in the reference list (6) since there was a citation error. There was a mistake in the original coding. --[[User:Z3289991|Robert Klein]] 13:20, 2 October 2011 (EST)

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Okay, the apropriate changes have been made to the history. I have saved the original copy on my computer of the history for future reference.--[[User:Z3289991|Robert Klein]] 07:36, 2 October 2011 (EST)

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I just got an email from Dr. Mark Hill, he prefers images from journal articles, so he'll probably remove them :( --[[User:Z3289829|Souti Khalil]] 23:17, 1 October 2011 (EST)

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2 images now, feel free to play around with them. --[[User:Z3289829|Souti Khalil]] 17:49, 1 October 2011 (EST)

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I just uploaded an image to the introduction, if you think its not appropiate or suitable there, feel free to replace it. also, let me know if their is any issue's with the copyright clearance.

--[[User:Z3289829|Souti Khalil]] 17:39, 1 October 2011 (EST)

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I think that sounds good Rob. I would also like suggest that the last two paragraphs in epidemiology moves to the signs and symptoms section, I think it would fit in a bit nicer there. Thanks Souti, did you want to do something in regards to the 'non-disjunction' sections? I was thinking we should fuse these together into one section (aetiology?), I also added all our non-disjunction pictures into the one section so it doesn't look too repetitive.

--[[User:Z3289066|Elisabeth Karsten]] 13:58, 1 October 2011 (EST)

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Hey Guys, Thanks for the nice feedback :). What I am proposing is that we replace, sorry, the long history paragraphs before the timeline with something similar to what I have written in my last comment. I will not change anything on the main project page without you guys approval first.

--[[User:Z3289991|Robert Klein]] 12:27, 1 October 2011 (EST)

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Hey guys, im also equally sorry for missing the lab on thursday. Rob, are you saying to replace the chunk of text in history with this paragraph and then maybe elaborate more in the timeline?

I'm going to work more on aetiology and history. I noticed that i have only contributed to 2 parts. So apart from looking for images and external links. Is there anything else i can do to help? any other parts you think we should add? Ill definately find a quote to add into the history.

--[[User:Z3289829|Souti Khalil]] 12:16, 1 October 2011 (EST)

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Added it where?? Do you mean added to the history, or put that instead? Because I think history has more than enough text already. That sounds good though what you've written.

--[[User:Z3289066|Elisabeth Karsten]] 11:27, 1 October 2011 (EST)

Cheers Liz! Also I went through the history and took aboard some of the critical comments that people wrote on our project wall. Leaving the timeline in place, how do you think the history section would look if we added the following:

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; gynecomastia, azoospermia, hyalinised and small testes, absent spermatogenesis, elevated levels of follicle-stimulating hormone (FSH) and hypogonadism. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>.
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient<ref name="PMID17415352"/>. This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref><pubmed> 13632697</pubmed></ref>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome<ref name="PMID3529433"/>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

--[[User:Z3289991|Robert Klein]] 11:17, 1 October 2011 (EST)

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No worries, looks good thanks rob. Yeh I went through and deleted a big chunk, but it still looks pretty long hey? I'll give that a go, thanks.
--[[User:Z3289066|Elisabeth Karsten]] 09:51, 1 October 2011 (EST)

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After reading the critique comments, I am proposing that we modify the introduction to something like:

First discovered in 1942, Klinefelter's syndrome is caused by the addition of one or more X chromosome(s) in affected males<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>. He depicted a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis. There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

People were suggesting that our original introduction is too long. What do you all think of this?--[[User:Z3289991|Robert Klein]] 07:19, 1 October 2011 (EST)

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Everyone,
Firstly forgive my absence from the last lab. It was Jewish New Year so happy new year to all!! Secondly, I will have another look at epidemiology, introduction and glossary and see if I can fix it up according to all the comments listed. I can get this properly done later today.
--[[User:Z3289991|Robert Klein]] 06:14, 1 October 2011 (EST)

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Hey guys, so we're now able to fix up the page for final submission. If you haven't already gone through the peer assessment, it would be good to do that. From what has been said I've changed the intro around a bit, let me know if I should change it more. I've also fixed up the references so there are no duplications. If you see any, just make sure to fix it up. If you're not sure how to do it I can show you in lab next week, or else just let me know and I can give it a go.

I was also talking to Dona during the lab, and we were thinking that (as was mentioned in the peer assessment) we probably only need one section on Non-disjunction, I know they say different things, but it might be better to combine the sections. I feel they would fit better in aetiology, then maybe the genetics section would fit better in pathogenesis? That was just my opinion really, if you've got any other idea just let us know.

We were also thinking (from looking at the other pages) we should get more interactive things, so diagrams, images, we've probably got enough tables. But a quote or two would look nice, I thought they were a good addition on the other pages. Maybe that would fit nicely into history?

Sorry about the long message, hope it helps and we can get this fixed up. Though I think we've already got a lot of good information. I plan to add a bit to the research section regarding "Future Research", and I'll be looking for more images today.
Good luck!!

--[[User:Z3289066|Elisabeth Karsten]] 12:22, 30 September 2011 (EST)

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==Peer Review==

A great Effort can been throughout the page. Some of these comments may be helpful.
*Introduction is well researched and referenced but I reckon it’s too long for introducing the topic.
* The History needs to be more organised in a way : like each year should have a separate paragraph. It will make it easier to read.
*Aetiology is well structured, however, I noticed the image needs a reference and a source.
*The Alignment of both images in the Pathogenesis section need to be adjusted to either sides.
* images are missing from the Signs and symptoms. In the table, Puberty and adulthood seem to miss the reference of the source.
* Great work on the table “Other Similar Defects” and the glossary.
* in General, Solid work on the page, references are enough evidence. One Last comment, avoid the repetition of the references(1,3) and some others need to be re-formatted ( 35,36) z3284061

'''Group 3'''

* The introduction is a little text heavy and might need to summarised
* The timeline could be longer
* Image in the Aetiology section is lacking a copyright notice
* The links in Aetiology are good
* An image would be good in Sign and Symptoms
* Pathogenesis needs more referencing
* Some information has been repeated in more than one section
* Links to the Glossary might be useful
* Overall its a good job
--[[User:Z3292953|z3292953]] 11:10, 29 September 2011 (EST)

'''''Klinefelter's Syndrome (Group 3) Peer Review:'''''

Introduction: Information needs to gloss over the entire page a little bit more. Also, the image used has not been referenced correctly and needs to have a copyright notice and the student template.

History: Seems a bit repetitive at first glance. Would it be possible to combine all of this information into the one table? Otherwise, information is good.

Epidemiology: Information is good, however the picture on the left hand side is too small. They have been referenced well.

Aetiology: Picture in this section is slightly ambiguous. Some readers may get confused. Possible more information as to what the picture is portraying. Also, reference the picture and make sure it has a copyright notice.

Pathogenesis: Good information and great hand-drawn images. Possibly need to be slightly larger and explained further. Only 2 references in this whole section?

Signs and Symptoms: Good, succinct list. However, maybe a bit more description? Also, images seem out of place. The images need to have correct referencing format and need to contain the student template. First image is too small.

Diagnosis: Good information. Image needs proper referencing and student template.

Management: Image needs a label at the bottom. Otherwise good image.

Other Similar Defects: This section was well done!

Current Research: Good information but possibly break up the text with a picture or two.
Well done and good luck with editing! --[[User:Z3290808|z3290808]] 10:41, 29 September 2011 (EST)

Klinefelter’s Syndrome – Group 3

* I thought the introduction was very thorough however it didn’t really flow and came across as rather disjunct. Maybe you could actually be a little briefer in this section as it does contain a lot of detail that could possibly serve better in other sections. Good use of image in this section.
* Good use of the table in the history section, maybe an image in this section would look nice also. Use of bullet points as suggested by other reviewers might help to give a more succinct overview, but I thought the writing in this section served well.
* Putting both images in the Epidemiology section on the right side of the page I think would look better, also the sizing looks like they could be matched.
* Aetiology is very well written. Good use of images.
* Some of the pictures need to be referenced correctly and also a little more detail once you click on the images is needed to help explain exactly what is being shown.
* Missing pics in Signs and Symptoms table. Maybe if its hard to find some you could remove this heading from the table and just have the images offset, as then it would not look incomplete.
* Some formatting issues in diagnosis section. I liked the inclusion of the movie clip.
* Current research could be better elaborated. Good explanation of papers however it doesn’t give an overall feel of what is happening in the field. Also the inclusion of future research direction could be an important point.
* Glossary a little incomplete.

--[[User:Z3288196|Z3288196]] 10:39, 29 September 2011 (EST)

'''Peer Review'''
You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

Oh and... YOU DON'T NEED X-CHROMOSOME IN GLOSSARY. The 16yo girl sitting in this lab knows what this means...
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:28, 29 September 2011 (EST)

Group 3:

The long introduction and history needs a pic.

The pictures in epidemiology are really small.

Links to the videos are a good idea.

There is an inconsistent amount of referencing throughout the various sections. Some sections have an excessive amount of referencing and others have just enough. Maybe 2-4 a section.

The references take up quite a bit of the page most probably because there are repeated references that have not yet been addressed.

z3332178 =]

'''Group 3:'''

*intro: the structure of this is a little confusing and it’s not really clear what you’re talking about. The flow of this section is really important – think ‘if I read it on a wiki page, would I read any further, or would I search a different page cos this was just too confusing?’ It might be good to start off your first sentence introducing the disease instead of talking about what happens in normal meiosis first. These few sentences that you put in the middle would be a good few opening sentences.. ‘One of these is known as Klinefelter's syndrome. This describes a syndrome where a person may have one or more extra X chromosomes. This is most commonly due to a process known as non-disjunction during meiosis,’ but start off with ‘Klinefelter’s syndrome is….’ But the content was good.

*history: this section was good with content and structure, but perhaps replace the second paragraph that has all the wordy dates with the timeline and stick your references there. Sometimes it works better with fewer words in a table than a chunky paragraph.

*epidemiology: making the pictures bigger would be nicer. Also theres a lot of info about stuff I would read under clinical manifestations which should be placed there instead.

*etiology: overall good section. The images were really useful. Loved the animation hyperlinks.

*patho: working on the ‘nondisjunction’ to be in one continuous line under the images would be easier to read on the viewer. Other than that, good section.

*signs and symptoms: good section. Easy to read. Concise.

*diagnostics, and the following subheadings: were all easy, well written, flow was good.

*glossary: really liked how you subheaded each part of the alphabet with the letters ‘A’, ‘B’ etc.

--[[User:Z3290558|z3290558]] 09:56, 29 September 2011 (EST)

'''Peer Review'''

:*The first paragraph is not necessary, talk about Klinefelter’s specifically not about sex chromosomes. This can be discussed further in the webpage.
:*Double spacing of paragraphs and other formatting looks awkward.
:*Great historic information but could be integrated into the timeline instead of having large paragraphs and a timeline.
:*Really liked “other similar disorders”. Great idea.
:*Some references need to be fixed so there is not double ups in the reference list.

--[[User:Z3217043|z3217043]] 08:55, 29 September 2011 (EST)

'''Peer Review'''

The wiki has overall interesting information and is well structured. You have also taken all of Mark Hill's suggestions and improved on the site a lot. Some issues:

:*Introduction is a little confusing and not very understood well. Should start off with Klinefelter’s description.

:*Some images are too small. To expand images while reading the wiki breaks up the flow, especially the table images.

:*I don't like the break-up of the alphabet letters in every title on the Glossary section; I find it very distracting.

--[[User:Z3293267|z3293267]] 08:53, 29 September 2011 (EST)

'''Peer Review'''

*Intro: Not a very good idea to introduce the disease with an overly simplified/unexciting image of meiosis, especially if you want the responder to keep reading. I’m sure there something more exciting to represent the disease.

*History: Thorough research, you just have to find a better way of representing it. Take the text, break it down and add it to the timeline. If I was given this to read I would look at the timeline and skip the text, it’s too much.

*Epidemiology: image: “Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png”. The png should not be left at the end of image and quite honestly the table is hard to understand with little explanation given. Wouldn’t people ask what is “ F(1,27= 5.9, p=0.02”? Either explain the table thoroughly or get rid of it.

*Aetiology: Animations were excellent! Perhaps use still-frames as images in this section, because the picture provided is a bit dull and looks very similar to the opening image.

*Pathogenesis: The two images look very similar; perhaps use different colours to indicate their differences. It will make the page more appealing also. The information is relative and easy to follow, although some information is overlapping with aetiology.

*Signs and symptoms: Love the table format- but more information is required. More detail on each section and corresponding images would improve it. Also there is no referencing in the “puberty” section.

*Management:“Action of Amoratase Inhibitors on Production of Estradiol.JPG” is not referenced.

*Other similar defects: It’s a lot more thorough than a few of the sections explaining the disease itself. I don’t think you need to be this descriptive in this section.

*Image/text ratio: need more interesting images (no more cell division images though), and also need to be more detailed in a few sections as mentioned above.

*Overall: Good job, but you still have some work to do.

--[[User:Z3290270|z3290270]] 02:35, 29 September 2011 (EST)

'''Group 3 Peer evaluation'''

*The introduction is good. It brief and informative of what t o expect in the page. The only criticism I have is that the historical background that was placed towards the end of the section, which should probably have been in the beginning or incorporated somewhere there.
*The History section is good, but probably too detailed. I think you can mix the timeline and history together and make this section a bit more concise.
*Epidemiology is a bit of a disappointment for me. There is a bit of information of the demographics of the disease, like prevalence, but I think epidemiology should go deeper into it, like talking about geographical distribution or if there is any race that are more inclined to developing the syndrome. Also this section ended up being an in-depth illustration of a patient’s clinical manifestation. Probably a few statistics on what percentage shows these different types of manifestation and figures some figures of the variation in mutation.
*The etiology section is very informative and I think it has all the information needed for that section. I just think that the arrangement of the information could probably be changed a bit. I think the genetics subsection is unnecessary, even though it does break the section up a bit and allows categorization of it. I just think that you could organise the ideas in this section better than what it already is. The image used here was very appropriate and aids the reader.
*I really like your pathogenesis section. It’s simple yet informative. It is very effective because the terms and concepts that you guys have here are not foreign to the reader because you have already introduced them beforehand, or explained it. Only downfall I guess is the referencing. There is only one section of your information that is referenced.
*Signs and symptoms are done well. You got away with just listing them because most of it is self-explanatory. I guess the only thing that will make this section amazing are some more elaborate images.
*Diagnosis section is done quite well, although the heading should be reconsidered to something like diagnostic test/procedure or something because the diagnosis is “klinefelter’s syndrome”. You also did a good job in incorporating what the tests are looking for, especially in the karyotyping bit. Unfortunately, this was not done for prenatal diagnosis methods, so a bit more information on this one. Finally, I don’t think the statistics need a whole subheading for it. It could just be part of an introduction to this section.
*I like the management section and the image that you used with it is used appropriately and very useful
*The other similar defects is informative, but I think that you went into far too much detail for it in a page dedicated for klinefelter’s syndrome. It is written well and the information in it are amazing though.
*I like the current research section because it says to the reader that the information on this page are up-to-date, giving the whole page credibility. What would probably make it better is a future direction kind of area, where you can put in some proposed theories or studies by researchers, and at the same time some of your own ideas of the direction where this syndrome should head into.
*I am not a big fan of glossaries, but it does look good
--[[User:Z3290841|z3290841]] 10:21, 29 September 2011 (EST)

'''Peer Review Assessment'''
*Overall, good use of sub headings and layout.
*Maybe start the introduction with the actual disease rather explaining the genetics behind it. Got a bit boring. However rest of it was well written.
*History section is well researched. Table is a good summary of the key events. Try and insert an image in this section to break up the heavy text and bring some color into the page.
*The epidemiology section contains information about clinical manifestations and appearances that can be included in a different section. Try and refine this section a little bit. Enlarge the two images in this section.
*Aetiology was well written. It might be a good idea to include some text below the student drawing included in this section explaining it. It doesn't make much sense at the moment.
*I liked the pathogenesis and sign and symptoms sections
*Liked his 'other similar defects' table. Explains the information quite well.
*Very well researched assignment.
--[[User:Z3291622|Z3291622]] 01:23, 29 September 2011 (EST)

'''Peer Review'''
* Picture under "management" is not explained.
* Introduction properly touches on all the topics elucidated later without crossing over too much.
* History is made relevant, linking it to Signs and Symptoms as well as Aetiology.
* Pathogenesis needs more references, as could Signs and Symptoms.
* The layout of Diagnosis At Birth is peculiar.
* Signs and Symptoms could use more demonstrative pictures.
* Glossary is fairly comprehensive.
* Use of related diseases section is interesting, but perhaps should be included within Diagnosis under "Differential diagnoses" or something similar....
--[[User:Z3290689|z3290689]] 00:28, 29 September 2011 (EST)

'''Peer Review for Group 3'''

*The first paragraph of the introduction could be inversed so it can actually start with what Klienfelters syndrome.
*Introduction seems a bit long, making it a bit briefer will capture the audience’s attention better.
*Within the history section the dates should be in bold so that it is easier to follow the information in this section. However, the history does give a good background to the syndrome.
*Table with major advancements is well done
*Epidemiology includes alot of information that doesn’t relate to epidemiological studies, and rather talk about clinical manifestations of people with the syndrome. Maybe put this type of information under another title.
*Figure 4 in the aetiology section should be explained more so that readers could understand what they are looking at.
*The genetics section under the aetiology is interesting, but is it necessary for it to be there, or how does that info link to Klienfelters Syndrome?
*Genetic pathogenesis is explained well. I think the two diagrams should go after the non-disjunction paragraph as it will make the page look better. Also you could talk about how this problem produces the problems for the patients throughout their life.
*Good use of table and dot points in the signs ans symptoms page. It will look good if you have a picture for all categories as you already have 2.
*In the diagnosis section, a little effort should be made to explain how karyotyping occurs as it will make that part better. Other than that the section is good
*I like the ‘other similar defects’ section as it allows the reader to compare and contrast klienfelters with other diseases
*Current research presents a picture to the reader about the current research area for klienfelters.
*Referencing MUST be fixed up as there is repetitive referencing seen in the list.

--[[User:Z3291317|Z3291317]] 23:43, 28 September 2011 (EST)

'''Group 3'''

Introduction: I think you need to explain what the disease is before you explain the genetics behind it. Also, this section seems more like a summary of the whole project. I think you could change it a bit to include more general information on the background of the disease before going into detail.

History: I think this section would be good if all the text was incorporated into the timetable and some pictures added to balance out the text.

Epidemiology: Good section overall however, the pictures could be a lot bigger.

Etiology: Good section but I think the picture needs a caption to explain what the diagram is referring to.

Pathogenesis: This section is clearly explained. The pictures are great but need to be bigger.

Signs and symptoms: The table is good but I think it would look much better if you added pictures for all the sections.

Diagnosis: Similar advice to most other sections- the text is good but I think you should add some pictures to demonstrate some of the abnormalities.

Management: The picture would be good with a caption to explain what the diagram means.

Defects: The table is good but a couple of the pictures are far too small.

Current research: Good section, but again, needs some pictures!
--[[User:Z3291324|z3291324]] 23:20, 28 September 2011 (EST)

Group 3

Hi, overall, a nice project page with interesting information.

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: Nice introduction, good flow and easy to read. However, image needs proper information and perhaps 'This disorder was first described by Harry F.' could be placed earlier on in the intro rather than in the middle
#* History: Nice section, very interesting
#* Epidemiology: First paragraph is good, but I feel the rest of this section doesn't quite belong here, such as the information on seizures, IQs, diagnosis. This section should focus on stats (sex/birth/ethnic/demographic/etc). Fig 2, 3 belong more in the signs and symptoms
#* Etiology: the '1:1000 male' contradicts the '1:500' given in epidemiology. Fig4 needs coyright information
#* Pathogenesis: Needs better referencing, also placing fig 5, 6 on either side doesn't look too good with the text. Perhaps place them below one another?
#* Signs: Seems a bit incomplete, it'll also be good to explain the image of 'pubertal gynecomastia'
#* Diagnosis: Sentence structure could be improved, ie. 'performed because physicians may suspect it because of clinical findings'. Information is interesting, but could be presented more clearly, perhaps in a table?
#* Similar defects: very nice, presented well with good information, easy to read
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Good images used with a nice range of self drawn images. However, lot of the images need to be formatted properly with required information
#Content is correctly cited and referenced.
#* overall referencing was well done, except pathogenesis needs more referencing
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* Nice range of references used
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
#* The information is there, but maybe from now til final assessment, you could do further research in all sections, as they do seem a little short.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* better page layout
* glossary: sorry, but I feel the alphabet subheadings here are not very effective as you have it in alphabetical order anyway

--[[User:Z3291643|z3291643]] 22:01, 28 September 2011 (EST)

'''Group 3:'''

•Good subheading structure, the page flows nicely

•Some parts of the introduction need to be reworded and it should start with an explanation of Klinefelter’s rather than the description of meiosis which is i think is unnecessary at the very beginning of the page.

•Detailed history in the text section, however is the timeline finished? Research after 1970 needs to be completed.

•Glossary needs to be completed, and i’m not sure if you need the separate headings for each letter in the glossary as it spreads it all out a lot.

•Lots of the references are repeated

--[[User:Z3332183|z3332183]] 21:25, 28 September 2011 (EST)

'''Peer Assessment Group 3 Klinefelter's Syndrome'''
*Your introduction is interesting and a good summary of the page
*The history is good however could use a picture
*The images under 'Epidemiology' have quite poor resolution, can hardly read them
*The rest of the page looks great and I have no more to add.
*It is easy to read, well balanced text and pictures and informative
--[[User:Z3308968|Tahmina Lata]] 20:54, 28 September 2011 (EST)

'''Group 3: Peer Assessment'''
* You have constructed an informative page about an interesting syndrome
* At this stage it's a little text heavy, so may be you can cut it down and add some pictures instead
* In the history section it would be great to see these dates from the table with the text blended in, so it's on chronologic flow.
* You seem to take it very serious with the mitosis or not communicating with each other because you have four pictures of mitosis in three different sections. One picture and a good explanation would be sufficient. Then you could use the rest of the space for other pictures.
* The table for signs ad symptoms is great, but looks a bid empty. So may be you can change the format or add some more pictures.
* May be you could write a bid more about therapeutic options. I would find that more important then "similar abnormalities"
* Good referencing through the section. Just change the "double referencing"
* Overall, you page has a lot of information, may be you can balance it a little more out, communicate so you don't have "double" information and a few more pictures would be great.
--z3279511 17:08, 28 September 2011 (EST)

'''GROUP 3 Peer Assessment: Klinefelter's Syndrome'''
*I feel that the introduction is too lengthy, it should be summarised a little more. Although the info is informative, its structure needs some work- grammar and punctuation should be reviewed and sentence structure could be improved
*Figure 1 could use a more descriptive legend
*Historical information is ok, maybe could be improved by extending the timeline to a more resent years, also an image wouldn't hurt, just to break up the text a little
*epidemiology could use some proof reading to correct minor grammar mistakes e.g. "Males born with Klinefelter syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes", sentence structure could also be reviewed so this section flows better (some sentences are short, but other than this, this section is informative
*Incidence is repeated twice, maybe could stick to one section, and it's different in each section (1 in 50 000 or 1 of every 1000 male births?)
*Aetiology (don't really know what this means), and the subheading "genetics" could be a better choice for the whole section, but info here is informative and understandable
*I do like the links made in Aetiology, the picture in this section could use a better legend and needs to be referenced properly (no copyright statement?)
*There is overlapping info in the Aetiology and Pathogenesis sections (both have Non-disjunction as subheading), and both have the same sort of images
*Table in signs and symptoms is too small should be a lot bigger so detail can be seen, it also needs to be referenced properly
*The info for signs and symptoms is good in a table, but it would be better if the table had colour so the reader can distinguish each section of the table
*diagnosis is informative

Overall:
*Reference list needs some work, some of the references have been repeated
*Project could be improved by finalising the glossary and maybe linking the words in the body to the glossary itself
*Images need to be referenced properly and some need more informative legends
*I feel some of the information is a little repetitive, maybe could read through and edit so it flows better
*subheadings and headings could be reviewed and re-organised so page flows better
*I do like the feature of links added throughout, maybe more would make it better

--[[User:Z3331556|z3331556]] 14:28, 28 September 2011 (EST)

'''Group 3 Peer Assessment'''
* Try to link your sentences in general - at times the reading is quite disjunct and difficult to read. Try to rewrite sections and see if it can be written in a more succinct manner.
* In general, keep the images on the right hand side of the page - I know you want to break things up, but if images are kept on the left then it disrupts the paragraph lining and makes the information difficult to track with the eye (just a minor thing, this is my opinion anyway)
* Some subsections just appear too short; is it really necessary to make a subsection for one or two sentences, as is the case of karyotyping? Try to implement all of the information into one paragraph
* The first image requires a proper reference to the work; is there any copyright information? And also protect your hand-drawn images - they are drawn excellently, but have no copyright information (unless you are happy with the images been used straight away by other students! :) )
* The current research section and possible treatment options section is far too brief; if this is a syndrome that causes many problems, then there should be a fair amount describing our direction of research and methods in which we can combat this syndrome. Try to find more information here!
* Overall, a good balance of the images and format, but reconsider the structure of paragraphs and subheadings so that the entire project has a better feel. Many sections feel like they have been started with great enthusiasm, but this has burnt out over time, giving the project a feel that some sections are just left incomplete. Try to fix this!
--[[User:Z3288827|Leonard Tiong]] 09:37, 28 September 2011 (EST)

'''Peer Assessment'''
*The first two paras of the introduction belongs in the genetics/etiology section. Need a broad intro to the actual syndrome and what happens in it. You don’t need to give a brief overview of all the sections, this isn’t an English essay.
*History- break up with bullet points?
*Figure 3 is a bit small – a bigger pic will look better I think
*Pictures in the Pathogenesis section look funny with the text – maybe have one under the other? It just squares the text in the middle and it looks odd.
*Don’t forget the missing pics in the signs and symptoms table
*History/timeline table might look better in purple – keep it consistent with the others.
*In the Current Research section, the 2nd paper that you have described is written with very colloquial language – can’t use that here! Maybe have a brief intro para about current research and where its headed etc, not just a description of papers. Also, maybe link them to other papers, e.g. This paper shows similar results to _______, surely there are similar findings in particular areas of research?
*Fertility picture needs to be in a ‘Figure’ box with a description and explanation of what it means.
--[[User:Z3332824|z3332824]] 23:30, 27 September 2011 (EST)

'''Group 3'''

*I think the introduction should be a little more concise
*History could work better if all the information was summarised in a table/timeline rather than having paragraphs then a timeline. *Also, I find it a little hard to believe that no findings have been made since the 1970s.
*Epidemiology would probably benefit with subheadings
*Signs and symptoms are nicely set out
*I like that you have added a comparison of other diseases
*Maybe add a few more researches from 2011 rather than 2010 (if possible)
*Overall, quite a good project with some minor adjustments needed

Group 3:

*Whilst I appreciate the introduction and its content, I feel an introduction doesn’t need to be of the same size as some of the other sections of the project. It is to give a mere idea of the condition.
*History could be broken apart with dot points or bolded dates instead. How about a picture of Harry Klinefelter?
*Aetiology picture has no link to the article or where it was found, and no copyright notice.
*Pathogenesis has very little references, surely more would have been used.
*Images in table are blank and a lot more references would have been used than shown.
*space out the subheadings so they don’t look disjointed in diagnosis.
* references have not been listed properly (various links for same article)
--[[User:Z3291423|z3291423]] 18:09, 27 September 2011 (EST)

Group 3: Klinefelter’s Syndrome
*overall look: inconsistent formatting, imbalance of text and images in some sections, appropriate headings used.
*introduction: very broad, maybe too much detail?
*history is well researched; I really like the timeline at the end which summarises the major advancements. But it is very short and ends in the 1970s. It could include current research/advancements.
*Epidemiology: could benefit from a few subheadings or breaks in the text.
*Aetiology: I really like the use of external links.
*Signs and symptoms: works well in a table format but not sure why some cells are coloured and others are not.
*Other similar defects: interesting addition to the webpage, allows audience to continue research. Also demonstrates extensive knowledge of the syndrome. Great idea!
*Minor adjustment: just for convenience, glossary terms could be linked
--[[User:Z3332327|z3332327]] 16:14, 27 September 2011 (EST)

'''Group 3 assessment:'''
*Introduction begins in a confusing manner should begin explaining the disorder Klinefelter’s syndrome before explaining the genetic component of meiosis. Where the image was explained though would be more beneficial if the introduction have an image of the founder of the syndrome within this section or within the history heading.
*History has clear structure with explained information of the progress with relation to the timeline of the syndrome, images would have been more useful within this sub heading to make livelier instead or too much text.
*Epidemiology detains the male component though could explain female areas related to syndrome as well figure 3 .
*Pathogenesis is organised with images placed in areas which bring upon confusion where fig 5 and 6 both linking to Non-disjunction, image placement beneath text would be better placement.
*Signs and symptoms could have a little more elaboration and/or more images
*Sub heading of diagnosis at birth needs to place either in the centre or down 1 sentenced to become more organised.
*References should remove any repeats and the links below should be manually added to the references either under another subheading or normally
*Glossary should be linked throughout, either linking the word to the glossary or even bolding the terms so no confusion for people without any background in the area can understand.
z3332250 23:43, 26 September 2011 (EST)

Group 3 Peer Review

*Well structured and organised
*Timeline seems odd that it ends at 1970? If further information cannot be found, try to present this in a different way
*Figure 2 and 3 could perhaps be a little bigger
*Should a copyright statement be included in some of the images?
*Signs and symptoms table is great
*Some duplication of information throughout page-unnecessary
*Video link is a nice extra
*Well balanced text, images, and tables/graphs
*Overall, a well written page and visually appealing
--[[User:Z3308965|Fleur McGregor]] 18:48, 26 September 2011 (EST)

===Comments on Group Project 3===

Group 3

*Introduction seems a bit wayward to begin with. Maybe introduce the syndrome first and then briefly explain meiosis, it just seems a bit indirect. I like how the intro touches on some aspects to be described later in the page but, good work.
*History section could be organised a bit better I think, the combination of text and timeline is good but there must be a balance, right now there’s a big block of text and a teeny timeline
*People might have already said this but I think the epidemiology section is too broad and covers topics outside of its section (clinically diagnosed characteristics and such)
*Aetiology – I definitely like this section, the image is perfect and relates to the non-disjunction paragraph, information provided here is clear and easy to understand.
*Pathogenesis – maybe consider reformatting the images so that the information under ‘Anaphase Lagging’ is easier to read, and the heading ‘Nondisjunctiom’ is not in the middle, would add to continuity and the flow of the entire page if all headings were aligned to one side
*Other Similar Defects – this table is really hard to read, but the information is good, although it does need to be referenced properly
*Nice glossary and current research headings, I don’t really see anything to fix. Good job guys.

--[[User:Z3331469|z3331469]] 06:58, 29 September 2011 (EST)

'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

--Z3389806 07:08, 26 September 2011 (EST)

'''Group 3'''

*Introducton: the beginning is a bit to abrupt, very nice image, otherwise good content

*History: very detailed information, useful timeline

*Epdidemiology: fig.3 would look better on the right side, the content is good

*Aetiology: no copyright information for the image, good use of subheadings.

*Pathodenesis: again, figure would look better on the right side, it disrupts the flow.

*Signs and symptoms: good table, the images look a little lost though, so maybe place them on the right edge, “age and intellect” could be bigger.

*Diagnosis: well done

*Management: good content, nice flow

*Similar defects: good content, but the structure could be better, maybe place the content in a table without the dots. Everything that belongs to e.g XO should start at the same hight

*Research: interesting section, well done

*Glossary: seems incomplete

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 12:13, 25 September 2011 (EST)

Group 3
* The first thing I noticed is that the project is very text heavy. Also- there are 4 images of mitosis. Is this really necessary? One is enough and you can use the other spaces to put other images in
* The introduction gives a nice, broad overview of the project. I understand immediately what is going to be said. But is there not an image of a patient to put here to draw the reader in? Maybe its just me that isn’t very excited about images of mitosis sorry.
* The history section would work better as a list of dates and names rather than a bulk of text
* Has there been no research since the 1970s? More recent findings need to be added to the history
* The epidemiology is very interesting- but there is a lot of clinical manifestations here that are described later. There is a double up in information.
* Signs and symptoms works well in a table- but more images of the condition would make it even better
* The comparison of other conditions is excellent! Great idea.
* Your information is there is just needs to be organised a little better and the fact that you have double ups on information and pictures indicates that there may not be any communication in the team- either that or laziness to find a different picture. Look forward to seeing your final project!

'''Group 3'''
* Good over all structure with the use of headings and sub headings. A very interesting syndrome and the page is easy to read.
* I think the intro could be condensed a little, as it should get straight to the point.
* I enjoyed reading the history section and good use of table and summary of history.
* I like figure 1, very nice that it was done by a student!
* figure 4 Maternal Non-Disjunction.. Is this a student drawn pic or did you use it from somewhere.. a little unclear.
* I was nice to see sign and symptoms tabulated, which made this section very easy to read and understand. good use of picture here. Could you find anymore relating to the signs and symptoms?
* I liked the addition of a movie link.
* The sub heading of diagnosis were very appropriate.
* Other Similar Defects- very interesting to add this in..
* Interesting current research: nice that it has been summarised.
* Make sure your reference list hasn't doubled up.
* Just for clarity it might be nice to use the same colour table throughout the page.
* It was good to see some of your pictures correctly labelled.

*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?
The genetics part is good though.
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.
*'''Management''': Looks good.
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.

'''Peer Assessment: Group Project 3'''
*The introduction is informative, however I think that the small paragraphs at the end detract from the section as a whole. It would be better to integrate these more so that they flow on from the previous text.
*The history section provides both detailed information and a timeline, which makes the historical stages easy to comprehend and refer back to.
*Is the image in the section on aetiology drawn by a student? If not, then copyright information and referencing needs to be included.
*In the section on diagnostic procedures, the image could be placed on the right for ease of reading.
*The figure in the signs and symptoms section and the figures in the epidemiology section are too small.
*Using colour borders in the signs and symptoms table would make it a bit clearer.
*The links to animations and a movie are great uses of additional material.
*Under the information in some of the images you have uploaded, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*The references should not be duplicated and can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
--[[User:Z3217345|z3217345]] 13:28, 27 September 2011 (EST)

'''Group 3 Assessment'''
*The Meiotic Non-disjunction jpg doesn’t have the proper citing or information about future referencing abilities.
*In the history section, I like how the occurances are both described in detail and set forth in an easy to read table format. Very organized.
*In the Aetiology section, where is the referencing for the Non-disjunction videos? Is video copyrighted?
*The Aetiology section and Pathogenesis sections seem to contain almost identical information. Are both necessary, or could they be combined/ one deleted?
*If you decide to keep the Non-disjunction videos, are the pictures in the Pathogenesis section necessary? Or do they just become redundant?
*In the Epidemiology section, both pictures need to be enlarged; they are so small I can’t make a distinction as to what’s on them.
*Signs and Symptoms- This section overall looks very good as far as information goes. The only thing I would suggest is to separate the different age sections a little bit more; their symptoms look to be running together from group to group. Also, try increasing the picture sizes, as they (especially the first one) is difficult to read.
*Again, for the video under Karyotyping, where is the referencing and copyright information on this?
*Action of Amoratase picture- This still needs to have the disclosure statement reguarding re-use and copyright guidelines. Also needs a descriptor sentence below the picture.
*Glossary- Shouldn’t there be references for these definitions?
*Both the Similar Defects and Research sections seem decent. Only suggestions:

-Similar defects chart: Try bigger pictures and sentences of less length.

-Research- Try adding a picture to the section to make it more aesthetically appealing
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
--[[User:Z3391078|Ashley Smith]] 14:00, 27 September 2011 (EST)

'''Group 3:'''
* The introduction is very lengthy, some parts feel as though they would be more appropriate in other sections. The image here fits nicely with the text but it could benefit from a more descriptive legend and needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>.
* In the history, you begin to use the short hand “KS” without an initially stating that this is the abbreviation for “Klinefelters syndrome (KS)”. The dates that are mentioned are very detailed although it ends in 1970, were there any other breakthroughs since then? A picture of Klinefelter would be a nice touch here.
* Epidemiology requires some proof reading as there are a couple of little mistakes and the images would have more of an impact if they were slightly larger.
* I like how you have linked figure 1 to the non-disjunction sub-heading under aetiology. The image in this section could benefit from a coloured legend, ie. Instead of saying “Blue circles are male cells”, in a box include an actual blue circle = male cells along with the other descriptions. It also needs to be properly cited.
* There is too much repetition between pathogenesis and aetiology, maybe discussion between these two students is needed to minimise repetition. Good hand drawn images but you need to include the student template as mentioned previously.
* Signs and symptoms would look better in a coloured table and with more images. I don’t think it is necessary to repeat the image comparing age and intellect here.
* Diagnosis; nice use of another form of media – a video. The abbreviation of KS in this section needs to be established first by placing KS after the first time you mention Klinefelters syndrome.
* Management is very concise and thorough
* Other similar defects; nice touch, it could look more appealing with the use of colour and larger images though.
* Current research is formatted nicely and flows well

'''Group 3 - Peer assessment'''

*The introduction is abit lengthy and choppy because some paragraphs are just 1-2 sentences. Maybe try to connect them into one paragraph and try to make it flow better.
*The history was quite informative maybe put the timeline at the top and the text at the bottom and maybe try to add more recent dates.
*Epidemiology - the use of figures are good and it is explained well in the text
*Aetiology - good idea in external linking images! the information is easy to easy as it is well structured
*Signs and Symptoms - the table is abit confusing to read, althought the information is well reduced
*Other Similar Defects - maybe the use of lines within the table would be better to separate the columns and rows because it is abit hard to read

--[[User:Z3330313|z3330313]] 19:50, 28 September 2011 (EST)

--z3290815 15:54, 28 September 2011 (EST)

'''Peer Review'''

* a lot of writing and so makes the wikipage interesting to read
* the image in the pathogenesis section needs fixing
* the image layout is not organised well
* needed to explain Klinefelter's disorder in simple terms. I could understand it but if it was explained in a more simple way it would be much better.

--[[User:Z3060621|z3060621]] 20:58, 28 September 2011 (EST)

'''Group 3'''
'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are present.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Under aetiology, it might be good to add a sentence or two about the cause of Klinefelter's Syndrome rather than just jump right into aneuploidy. I understand that it is the aetoilogical agent in Klinfelter's but indicating it as a cause would be good to kinda give the reader a 'flag'. It is not necessary to add the information about aneuploidy in the introduction as i think you could move that section down to a more appropriate part. If need be, just mention aneuploidy as a cause in the introduction rather than dedicate the first paragraph to it in the intro.

'''*Content is correctly cited and referenced.'''
Maternal Non-Disjunction.PNG needs some references, Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG, Pubertal gynecomastia.jpg, Immunoglobulin levels in 15 girls with Turner Syndrome.png and Karyogram of male with 47, XYY Syndrome.png needs to be correctly referenced. duplication of references need to be fixed. More references need to be included when there is a huge chunk of text or it looks very much like you got everything from one source only.

'''*The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.'''
Good drawings - explanations are understandable.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
There is a significant reference list but not enough in-text referencing.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
A lot of content on genetic problems, maybe put something in about development of embryo (if applicable)?

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has shown development and editing to be based on the above guidelines although some smaller details could be fixed.

--z3329495 21:11, 28 September 2011 (EST)

==Discussion==

----

Hey i have been looking for a profile pic for some time and none have come up. So prob better if you don't look for it because I am afraid that you will waste time. Nice! birthday cake :) I should do that for my dad's bday which is coming up.
Anyways see you tomorrow
--[[User:Z3289301|Dona Cho]] 23:55, 21 September 2011 (EST)

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Hey Dona, thats a good idea! i like all the pics that you have added, and pathogenesis looks good! I just baked my dad a birthday cake and planning on doing some work on this now. So i will probably be up for a while. I am also looking for pics of H. Klinefelter. Good work!--[[User:Z3289829|Souti Khalil]] 21:12, 21 September 2011 (EST)
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I am looking for a profile picture of Mr Klinefelter. I think it will be good to put one in in the introduction section. I am having trouble finding any - but you do come across one pls put one up -I think it will look great!
--[[User:Z3289301|Dona Cho]] 20:19, 21 September 2011 (EST)

----

Guys I thought that it would look good if all the images were order 'figure 1, figure2...'
Just so that it all looks uniform
Hope your ok with it but if you don't like it you can just change it back.

--[[User:Z3289301|Dona Cho]] 17:52, 21 September 2011 (EST) :)

----

That looks interesting, but I'm not really up to adding any of that tonight. Feel free to add whatever you like.
--[[User:Z3289066|Elisabeth Karsten]] 22:57, 14 September 2011 (EST)

Hi guys ;)

I was just reading some stuff - found some interesting info related to management (I think it is liz?)

The part of the review is as follows:

'Decreased energy and libido, which are associated with postpubertal testosterone deficit, improve with hormone therapy and often are accompanied by improved confidence and sense of well-being.Androgen therapy should be started when there is direct laboratory evidence of a testosterone deficit or when hypergonadotrophism, which suggests such a deficit, is present. This may occur by the time the patient begins middle school...

Because gynecomastia predisposes men to breast cancer—the frequency of breast cancer is 20 to 50 times greater than in men who do not have Klinefelter syndrome1,2—monthly breast self-examination should be encouraged. If necessary for cosmetic reasons, gynecomastia may be treated surgically.'

The review also mentioned something about 'cryopreservation' so that the precious sperm can be stored and used for later IVF.

If the above sound interesting, it might be good reading the review article (particularly the management section. Follow the link below for the review.

http://www.aafp.org/afp/2005/1201/p2259.pdf

ps. I dont think I will be sleeping much tonight!!

--[[User:Z3289301|Dona Cho]] 22:32, 14 September 2011 (EST)

----

I don't think we can use those pictures, unfortunately. Safest to stick with papers and hand-drawn I think. The timeline looks really really good. If anything, I would be inclined to put a bit less info in the main bit of history and focus on that time line. I think it's a nice visual respresentation of the information.
--[[User:Z3289066|Elisabeth Karsten]] 21:17, 14 September 2011 (EST)

----

I found this website which has alot of picture's of KS, and there are only a few copyright statements, can we use them? [http://carregwenimages.com/klinefelters-syndrome-pictures]

Haha, I just saw them! thanks for that! I just edited the history and the timeline. Is the information in the timeline just repetitive of what i have written, should i just remove it? --[[User:Z3289829|Souti Khalil]] 20:09, 14 September 2011 (EST)
----

It did end up happy in the end lol. Yeh they look really good. We're allowed to add links to our page, so I think that'd be best. I'll put those on now. Thanks!
--[[User:Z3289066|Elisabeth Karsten]] 18:46, 14 September 2011 (EST)

Thanks for fixing up the table in signs and symptoms, it looks great!

That video was mean, i was eating when i watched it and i felt so sorry for the little boy, i couldnt watch the rest. :(

If you think we need an animation i found these two websites, but i have no idea of how we would put them on to our page.

[[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm]]
[[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm]]
--[[User:Z3289829|Souti Khalil]] 18:09, 14 September 2011 (EST)

----

That video is so funny! I was laughing to the point of tears while watching this! I don't think Dr. Hill would be too happy if we added the video to our webpage though. Great job Liz once again with the editing. Keep up the good work!--[[User:Z3289991|Robert Klein]] 15:22, 14 September 2011 (EST)

----

Hey everyone, I just uploaded our 1 Wikipedia image. It's the karyotype of Klinefelter's syndrome. If anyone founds anything better on Wiki, just make sure you say something and take that one off.
--[[User:Z3289066|Elisabeth Karsten]] 09:52, 14 September 2011 (EST)

So I found this video, it's super cute and lame. But I think it's a nice representation? Not sure how applicable it is though... http://www.youtube.com/watch?v=6q2JxMDaNys
--[[User:Z3289066|Elisabeth Karsten]] 10:08, 14 September 2011 (EST)
----

[[File: Signs and Symptoms by Age Group.PNG|right|300px| Signs and Symptoms by Age Group.PNG|thumb]]

Thanks Liz! I really loved the intro and the picture that you created! Maybe we don’t have to remove it, however I will also be on the lookout for a picture which may better suit the introduction. In the meantime, I was thinking maybe we should order the subsections better, for example; Introduction, History, Epidemiology, Aetiology, Pathogenesis, Signs and symptoms, diagnosis, management, other similar defects and then current research. I just think we should explain the cause and pathogenesis of the disease before the signs and symptoms and diagnosis.

Lastly, I found a table on a website and have created a similar one on signs and symptoms. I'll just upload it here, and we can decide if we want to use it.

That is all. --[[User:Z3289829|Souti Khalil]] 13:13, 12 September 2011 (EST)

That table looks really really good, though it could be easier if we upload it like the other table I put up, as opposed to a picture. I'm happy to do that if you like. And yeh that order looks good too, I'll change it now and if anyone disagrees they can change it back. --[[User:Z3289066|Elisabeth Karsten]] 22:29, 12 September 2011 (EST)
----

Our page is starting to looking really good!! I just fixed up the aetiology, it may need more work to be done though. Liz the picture i made, is really similar to the one you have in the introduction, is it too much?? Sorry about the delay in uploading it. --[[User:Z3289829|Souti Khalil]] 00:50, 12 September 2011 (EST)

That's fine, I kind of expected that. You use it since it fits in with your topic and I'll do another one for the intro. Aetiology looks really good, nice work!

--[[User:Z3289066|Elisabeth Karsten]] 09:07, 12 September 2011 (EST)

----
Hey Liz, Great job with the editing! It looks really good. I will keep on the lookout for gathering more information. --[[User:Z3289991|Robert Klein]] 20:31, 11 September 2011 (EST)

----

Hey everyone, I've just fiddled with the formatting of the page a bit. If you don't like it, of course feel free to change. I also changed the formatting of the table t make it a bit clearer to read, if you preferred the old one though I've saved a copy of it so just let me know. Just looking at the page, some things in epidemiology I think would fit a bit better in signs and symptoms; and eitiology and pathogenesis are a little repetive of each other which I guess we should of expected. But we'll be able to discuss it properly on this coming thursday.

--[[User:Z3289066|Elisabeth Karsten]] 20:24, 11 September 2011 (EST)

To help out a bit, I found some links to articles that are 'Open Access'. This should save time for you guys:
http://www.springerlink.com/content/g68408vq74752421/fulltext.pdf
http://psy.hull.ac.uk/Staff/t.jellema/VantWout_PlosONE.pdf
http://www.autismresearchcentre.com/docs/papers/2011_BCetal_Plos%20biology_unsolvedmystery.pdf
http://www.ojrd.com/content/pdf/1750-1172-5-15.pdf
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020292
http://www.hogrefe.nl/fileadmin/user_upload/Documenten/PDF/Wetenschappelijk_onderzoek/Bruining_et_al_-_Dissecting_clinical_heterogeneity_of_ASD_through_genotypes.pdf
http://www.ijponline.net/content/36/1/36

Hope this helps!--[[User:Z3289991|Robert Klein]] 12:23, 9 September 2011 (EST)

Looks good, thanks rob.

--[[User:Z3289066|Elisabeth Karsten]] 20:24, 11 September 2011 (EST)

----

I had to remove the photo from 'signs and symptoms so that I can confirm it's copyright restrictions. Sorry about that. --[[User:Z3289991|Robert Klein]] 07:44, 9 September 2011 (EST)

----

I edited the Epidemiology and fixed it up as best I could. As well, I found and added a picture to the signs and symptoms section to make it a little clearer. I still seem to be having difficulties with formatting. If anyone comes across charts that I can use for Epidemiology, that would be much appreciated. I still can't find anything that I can use. I will fix up the 'other similar defects' section and have it ready very soon. --[[User:Z3289991|Robert Klein]] 06:39, 9 September 2011 (EST)

----

Hey guys, sorry I've been a bit MIA recently. But yeh I agree totally, I was planning to finish off the intro once everything else is finished, but for the moment I'll make sure I'll finish off my other sections.
And yeh you're ideas re:tables and diagrams sounds great. I'll have a go at drawing a couple on paint as well
--[[User:Z3289066|Elisabeth Karsten]] 21:39, 8 September 2011 (EST)

----
Good idea Souti! As well as that, I will retype my sections and try and fix them according to what Dr.Hill wishes. Maybe for treatments, you could speak about the drugs used to manage the condition. We do need to edit the other sections and add much more content and diagrams. Perhaps a few handrawn diagrams wouldn't go astray?--[[User:Z3289991|Robert Klein]] 18:40, 8 September 2011 (EST)

----
Hey guys, I noticed earlier today that Mark Hill has put comments on our page that we need to change and improve. So i'm going to take out 'case study', and replace it with 'treatments'. What do you guys think? Make sure you have a look at what he has said.
--[[User:Z3289829|Souti Khalil]] 17:44, 8 September 2011 (EST)

----

Rob, 'Other Similar Defects' is looking great! I am committing the next couple of hours to Klinefelter's syndrome. Do you guys think we could elaborate a bit more in the introduction, just to give a larger scope of our disease?

--[[User:Z3289829|Souti Khalil]] 11:48, 8 September 2011 (EST)

----

I added images to 'Other Similar Defects'--[[User:Z3289991|Robert Klein]] 07:55, 7 September 2011 (EST)

----

I have constructed a table for Other similar defects! I think that it should be alright, however there may not be enough info so the conditions may not properly be explained. We are still waiting on a table for signs and symptoms as well as a diagram for pathogenesis--[[User:Z3289991|Robert Klein]] 10:01, 6 September 2011 (EST)

----

What we should do is add a table to 'similar defects', a diagram for pathogenesis, a and a table for signs and symptoms--[[User:Z3289991|Robert Klein]] 12:49, 1 September 2011 (EST)

----

Glossary, Epidemiology and Similar defects have all been added. Let me know if anything else needs to be done!--[[User:Z3289991|Robert Klein]] 06:04, 1 September 2011 (EST)

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Alright Everyone,
For the different genotypes dotpoint, I will cover that when I complete the section to do with 'similar defects'. I have fixed up the referencing system. --[[User:Z3289991|Robert Klein]] 13:53, 27 August 2011 (EST)

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Hey guys,
I have included a list of things that Mark Hill emphasised in regards to our group project in the lab today;

- Different genotypes

- Animal models

- Review articles

- Importance of how the disease comes about (pathogenesis).

So, by next Thursday our main page should have plenty of content under each subheading. 
--[[User:Z3289829|Souti Khalil]] 14:14, 25 August 2011 (EST)

----

Hey Guys,
I have added a discussion tab for any enquires and updates on the progress of our assessment, as well as a referencing tab (or whatever they are actually called) at the bottom of the page. So for each section, if anyone finds relevant articles/images etc. they can place it there.
Oh, and please remember to add new content to the top.
--[[User:Z3289829|Souti Khalil]] 00:53, 18 August 2011 (EST)

----

Hey Guys,
Sorry to be a bother. I am having trouble referemcing properly in the Wiki format, as what can be seen in my Epidemiology piece and also my messing up of the reference list. Would one of you mind showing me how to fix this problem? Thanks so much and I will have the piece on 'other similar defects' prepared by Saturday. The glossary will be uploaded on Monday.
--[[User:Z3289991|Robert Klein]] 05:40, 18 August 2011 (EST)

----

'''Referencing'''
PMID is the reference number that you need

without the ':' will act as an link to the article
--[[User:Z3289301|Dona Cho]] 12:51, 25 August 2011 (EST)

==References==

If you find any good papers relating to someone elses topic, you can put them under these subheadings to help out.

Hey guys! this is a publication which seem to be pretty good!!

http://www.nichd.nih.gov/publications/pubs/klinefelter.cfm
--[[User:Z3289301|Dona Cho]] 12:54, 25 August 2011 (EST)

===Description/Introduction===

===History===

Natural history of seminiferous tubule degeneration in Klinefelter syndrome<ref><pubmed>16172111</pubmed></ref>

===Signs and Symptoms===

===Epidemiology===

Abramsky L, Chapple J.47, XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn. 1997;17:363–368.

Bojesen A, Juul S, Gravholt CH.Prenatal and postnatal prevalence of Klinefelter syndrome: anational registry study. J Clin Endocrinol Metab. 2003;88:622–626

[http://www.aafp.org/afp/2005/1201/p2259.pdf Klinefelter Syndrome]

===Diagnosis===

Hey guys, it's Dona. I put my name down for this section. I will try to get mine done by the end of this week. :)

--[[User:Z3289301|Dona Cho]] 17:23, 24 August 2011 (EST)

===Treatment===

===Etiology===

===Pathogenesis===

===Case Study===

===Similar Defects===

===Current Research===
http://www.ncbi.nlm.nih.gov/pubmed/7446531
Check this out!!--[[User:Z3289991|Robert Klein]] 05:03, 1 September 2011 (EST)

<ref><pubmed>21342258</pubmed></ref>

===References===
<references/>

==Pictures==
[[File:Magnetic Resonance of Head MRI from patient with Down Syndrome and Klinefelter's Syndrome.jpg|thumb|Magnetic Resonance of Head MRI from patient with Down Syndrome and Klinefelter's Syndrome]]

--[[User:Z3289829|Souti Khalil]] 23:57, 17 August 2011 (EST)

[[File:Klinefelter's Syndrome.jpg|thumb|center|Klinefelter's Syndrome]]

--[[User:Z3289066|Elisabeth Karsten]] 23:31, 13 August 2011 (EST)

[[File:Overview of human testicular sample from a patient with Klinefelter's syndrome.png|thumb|center|Klinefelter's Syndrome patient testicular sample]]

--[[User:Z3289991|Robert Klein]] 10:17, 16 August 2011 (EST)

[[File:Kleinfelter syndrome.jpg|thumb|center|Facial dysmorphic features in a child with double aneuploidy—Down syndrome and Klinefelter syndrome]]

--[[User:Z3289301|Dona Cho]] 20:35, 17 August 2011 (EST)

==Topic Choice==

Hey guys, so after having a look at that list I quite like the sound of
*Anencephaly or
*Klinefelter's syndrome

There's loads of resources for Klinefelter's syndrome, but I think Anencephaly sounds really interesting. It's a type of neural tube defect, so we may even be able to do that as a topic - neural tube defects (it's on the list as well).
Just let us know what you think, thanks guys!

I've just attached a review for each

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

[http://www.ncbi.nlm.nih.gov/pubmed/21110233 Neural Tube Defects] or [http://www.ncbi.nlm.nih.gov/pubmed/17089587 Anencephaly]

--[[User:Z3289066|z3289066]] 09:32, 6 August 2011 (EST)

Hey Everyone,
I am leaning towards Klinefelter syndrome as it seemed interesting to learn about. I found a couple of articles on the internet which explore more the epidemiology of the condition amongst the population. Liz, I read through your artiles and they were quite interesting in the way that they explored the genetics behind the condition. We will be able to perhaps link these in with the epidemiology to make our argument more convincing.

Below is a review article:

[http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/(SICI)1097-0223(199909)19:9%3C808::AID-PD637%3E3.0.CO;2-B/pdf]

The Research Article:

[http://jcem.endojournals.org/content/88/2/622.full.pdf+html]

Both articles explore more the epidemiology of klinefelter's syndrome as I felt that it would be interesting to look at its prevalence, and frequency of distribution within a population. The first review article that I hasve linked to explores the frequency of Klinefelter's syndrome in a population along with various other genetic anomalies.

--[[User:Z3289991|z3289991]] 07:02, 9 August 2011 (EST)

Yeh that sounds good to me, if anyone has any objections just let us know. We can figure out exactly what we want in the page on thursday, but yeh should def's talk about the epidemiology.

--[[User:Z3289066|z3289066]] 14:53, 9 August 2011 (EST)

Hey guys!

I think that Klinefelter's syndrome is definitely an interesting disease and it has lots of resources. I think we still need a plan B though, a few other diseases which I thought were really interesting are;
- Thalassaemia
- Anencephaly (good pick Liz!)
- Spina Bifida
I found a really good review article on Klinefelter’s syndrome, although it’s pretty dated.
[http://archinte.ama-assn.org.wwwproxy0.library.unsw.edu.au/cgi/content/full/158/12/1309]
[http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/ajmg.b.30163/pdf]

I shall see you all thursday!

--[[User:Z3289829|z3289829]] 22:15, 9 August 2011 (EST)

Hey guys, this is dona - I guess I am the last one to write on the board (sorry!)

I personally like the topic; neural tube defects. Reasons are 1. there is so much information because it is an umbrella term that includes many conditions like spina bifida and anencephaly
and 2. we will be learning the developing of the neural tube next week in lecture - so it will not be difficult to understand the etiology of neural tube defects

Here are the links:

review article [http://www.ncbi.nlm.nih.gov/pubmed/10899792]

research article [http://www.tandfonline.com.wwwproxy0.library.unsw.edu.au/doi/pdf/10.1080/19485565.1991.9988793]

p.s Hey could everyone identify themself by writing their name before writing on this discussion forum, that way people know whose talking. (please)

--[[User:Z3289301|Z3289301]] 17:23, 10 August 2011 (EST)

===Sections===

*Description/Introduction - Liz
*History - Souti
*Signs and Symptoms - Dona
*Epidemiology - Rob
*Treatment - Liz
*Eitology - Souti
*Pathogenesis - Dona
*Similar defects - Rob

I was thinking it'd be good to also do a topic on recent research, I'm happy to do that one, and should also do a glossary. So we should have someone finalise that, but it'd be really helpful if everyone could just add words in they think would be good as you go. Does anyone want to volunteer for editing that? Just put your name in the spot below so everyone knows.

*Recent research - Liz
*Glossary - Rob
*Diagnosis - Dona
*Case Study - Souti

--[[User:Z3289066|Elisabeth Karsten]] 12:15, 13 August 2011 (EST)

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Hey Guys,
I have uploaded an image to the Epidemiology section of the Group webpage, however it appears to have distorted the whole webpage in that all the other categories below epidemiology have been pushed to the side. Also, I am having trouble trying to enlarge the image. Do you know how I can fix this problem? The table was referenced appropriately.
Cheers

--[[User:Z3289991|z3289991]] 10:14, 13 August 2011 (EST)

Hey, yeh that should be fine for the moment, don't worry too much about the formatting. You can fix it, but it'll be easier to do once there's text there too move around it.
There should be a page explaining all the details about picture formatting, but I can't qutie remember how to do it off the top of my head. Is that the size of the original image? Because that could be part of the problem.

--[[User:Z3289066|Elisabeth Karsten]] 12:09, 13 August 2011 (EST)

Oh I've just realised what's happened, see how you've put the file name then "thumb"? The default for thumb is to make it slightly smaller and move to the right where it will wrap around whatever text is there. You can try [File name|thumb|left|name] if you want it on the left, or else instead of 'left' you can say 'center'. But it's gotta be 'center', not 'centre' (I think). Or else you don't have to use thumb at all, and just leave it out completely.

Hope this helps.

--[[User:Z3289066|Elisabeth Karsten]] 14:02, 13 August 2011 (EST)

Thanks Liz,
You know what? I will add some text during next week and then play around with the formatting. You are right in your first comment, because that way I can format the picture and text properly. Thanks so much for your help though.
--[[User:Z3289991|Robert Klein]] 15:21, 13 August 2011 (EST)

----
==Peer Assessments==

* Great amount of depth, you have covered each subheading quite well
* It was great to see a comparison to other similar defects
* Non-disjunction is discussed twice, can it be summarised into just the one section?
* In the signs and symptoms section, the images seem to be arranged in a disorderly fashion, maybe place them elsewhere. Also your image comparing age and intellect is extremely small. The sizing of a larger majority of your photos needs to b adjusted
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* There were only two examples of management strategies, are there anymore out there? Maybe you could do a comparisons table for this section
--[[User:Z3332629|z3332629]] 15:23, 22 September 2011 (EST)

2011 Group Project 3

2011-10-10T09:58:33Z

Z3289066: /* Current Research */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|Figure 1: 47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in more detail below and portrayed in [[Media: 47,XXY Klinefelter's Syndrome.jpg|Figure 1]]. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|180px|Figure 3: The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|Figure 4: Risk factors associated with male breast cancer|thumb|right]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. [[Media: Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|Figure 3]] is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with Klinefelter’s Syndrome compared to normal males. It has also been suggested that men with Klinefelter’s syndrome are 50% more at risk of being diagnosed with breast cancer, as shown in [[Media: Risk factors for male breast cancer.JPG|Figure 4]].<ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 500 male births<ref name="PMID17062147"/>, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Pathophysiology==

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb|300px]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Related Links==

'''Internal'''

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

'''External'''

[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | [http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet]

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
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--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

A maternal infection of rubella during the second trimester has been known to cause deafness in the neonate.

''Identify 3 factors that contribute to poor neonatal drainage of the middle ear.''

Normally, the Eustachian tube aerates the middle ear and clear mucus from the inner ear into the nasopharynx. The neonatal Eustachian tube is not yet fully developed, and so can have reduced middle ear drainage.

1. The tube is quite short

2. It is angled horizonally, and so drainage is not entirely effective

3. In adults two muscle are active in keeping the tube open, in neonates only one is active

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg WS1 - OMIM]

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-09T10:38:58Z

Z3289066: /* Lab Ten */

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

A maternal infection of rubella during the second trimester has been known to cause deafness in the neonate.

''Identify 3 factors that contribute to poor neonatal drainage of the middle ear.''

Normally, the Eustachian tube aerates the middle ear and clear mucus from the inner ear into the nasopharynx. The neonatal Eustachian tube is not yet fully developed, and so can have reduced middle ear drainage.

1. The tube is quite short
2. It is angled horizonally, and so drainage is not entirely effective
3. In adults two muscle are active in keeping the tube open, in neonates only one is active

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg WS1 - OMIM]

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-09T10:21:42Z

Z3289066: /* Lab Ten */

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

''Identidy 3 factors tht contribute to poor neonatal drainage of the middle ear.''

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg WS1 - OMIM]

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-09T10:21:19Z

Z3289066: /* Lab Ten */

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

''Identidy 3 factors tht contribute to poor neonatal drainage of the middle ear.''

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

Waardenburg syndrome (type 1) is characterised by a number of features including varying degrees of deafness. It is due to the gene PAX3 which is present at the locus 2q36.1. [http://omim.org/entry/193500?search=Waardenburg%20syndrome.&highlight=syndrome%20waardenburg|WS1 - OMIM]

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-09T10:05:40Z

Z3289066: /* Lab Eleven */

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Ten==

''Besides fetal alcohol syndrome, identify another envirnomental teratogen that can lead to hearing loss.''

''Identidy 3 factors tht contribute to poor neonatal drainage of the middle ear.''

''Identify 1 genetic abnormality that affects hearing development and link to the OMIM record.''

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

Talk:2011 Group Project 3

2011-10-09T05:14:27Z

Z3289066: /* Discussion */

[[2011_Group_Project_3|'''Group 3''']]: [[User:z3289066]] | [[User:z3289301]] | [[User:z3289829]] | [[User:z3289991]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_3_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_3_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Discussion==
Were we not planning to just replace pathogenesis with pathophysiology?

--[[User:Z3289066|Elisabeth Karsten]] 16:14, 9 October 2011 (EST)

Also guys, i was thinking that Pathophysiology should fall under the section on 'Pathogenesis'. What do you all think? My logic is that it will keep our webpage in a sequential order with aetiology, pathogenesis, pathophysiology etc...

I will add the section now and if you guys don't agree, you can always change it. --[[User:Z3289991|Robert Klein]] 11:31, 9 October 2011 (EST)

----

Hey Souti,
I am quite happy with the changes. Might I suggest that under aetiology you change all the figure numbers, so for example, label the first figure in that row of figures under aetiology as figures 5-?--[[User:Z3289991|Robert Klein]] 11:28, 9 October 2011 (EST)

----

Hey guys, I just changed a few things in epidemiology, all I did was put the images to the right and number them figure 3 and 4. If you guys think it is best to go without figure 1, figure 2 ... then please feel free to change it.
I also changed;

“Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.
It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer [18] “

To

“Figure 3 is a graph adapted from recent studies, demonstrating the emotional response to stimuli of men with Klinefelter’s Syndrome compared to normal males. It has also been suggested that men with Klinefelter’s syndrome are 50% more at risk of being diagnosed with breast cancer, shown in Figure 4.”

Feel free to play around with what I’ve done. I personally prefer to number images, what do you guys think?
--[[User:Z3289829|Souti Khalil]] 23:00, 8 October 2011 (EST)

----

Oh did he? I didn't realise. It can't hurt to change it. Ok no worries.

--[[User:Z3289066|Elisabeth Karsten]] 13:54, 7 October 2011 (EST)

Thanks a lot Liz! i'm currently at uni and i will be working on this tonight and during the weekend. Also, i noticed that you tweaked the links section, do you think Mark Hill will mind if we do it this way, as he did specify to have a section called 'Related Links'. --[[User:Z3289829|Souti Khalil]] 13:00, 7 October 2011 (EST)

----

Pathophysiology -

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/21655260 This ones about the psychophysiology of having an additional X chromosome

http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1651-2227.2011.02246.x/pdf That's about the generally clinical features, with reference to pathology. It's got some good images, so I've requested permission for their use

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20014371 This one assess the differences of cognitive function of XXY and YYX patients - not sure it would be overly useful though

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20014369 Impact of XXY on cognitive function

I'll let you know if I find anything else

--[[User:Z3289066|Elisabeth Karsten]] 11:35, 7 October 2011 (EST)

----

Haha, Dona can you see this?? Robert, Liz and I were talkingabout our group page and we thought that it may be better if we collate aetiology and pathogenesis, so there is no repetition. and then maybe add a pathophysiology section. I dont mind working on it. What do you think Dona?--[[User:Z3289829|Souti Khalil]] 12:10, 6 October 2011 (EST)

----

Okay, so the page has undergone some reformatting. Hopefully this will look better, as Souti and Liz have been reorganising the content.--[[User:Z3289991|Robert Klein]] 11:30, 6 October 2011 (EST)

----

Sounds good!! i will definately elaborate more in genetics and hopefull find an image to put there.
--[[User:Z3289829|Souti Khalil]] 10:25, 6 October 2011 (EST)

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I think that non-disjunction and genetics should be aetiology instead of pathogenesis. However Souti, you need to elaborate slightly more on the genetics.
--[[User:Z3289991|Robert Klein]] 10:23, 6 October 2011 (EST)

----

Thanks Guys! The necessary changes to the Epidemiology have been made. See you all tomorow
--[[User:Z3289991|Robert Klein]] 15:55, 5 October 2011 (EST)

----

Hey Liz, thanks, I think the history section is just about complete. I took into consideration all the peer reviews and changed a few things, however let me know if you think anything else needs to be done there. Epidemiology looks good rob!! Also, the picture in the introduction was just something that i found, but if you find a better image feel free to change it. I'll try to work on non-disjunction and aetiology later tonight. See you all tomorrow!

--[[User:Z3289829|Souti Khalil]] 13:49, 5 October 2011 (EST)

----

That looks really good rob, nice work. The picture in the intro is nice, but it doesn't have a reference and we do already have an image of the Klinefelter karyotype in the Diagnosis section. I'll see if I can find something else for the intro. The timeline for history looks really good.

--[[User:Z3289066|Elisabeth Karsten]] 13:24, 5 October 2011 (EST)

----

Hey Guys,
I tried to play around with an idea for epidemiology. Below is my idea. Note: I have changed nothing from Epidemiology on the main project page yet.

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]
One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.
A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.
Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.
[[File:Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png|thumb|left|Figure 3. The average intellect of boys with Klinefelter's Syndrome differs from that of normal males]]

--[[User:Z3289991|Robert Klein]] 13:40, 2 October 2011 (EST)

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I have amended the mistake in the reference list (6) since there was a citation error. There was a mistake in the original coding. --[[User:Z3289991|Robert Klein]] 13:20, 2 October 2011 (EST)

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Okay, the apropriate changes have been made to the history. I have saved the original copy on my computer of the history for future reference.--[[User:Z3289991|Robert Klein]] 07:36, 2 October 2011 (EST)

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I just got an email from Dr. Mark Hill, he prefers images from journal articles, so he'll probably remove them :( --[[User:Z3289829|Souti Khalil]] 23:17, 1 October 2011 (EST)

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2 images now, feel free to play around with them. --[[User:Z3289829|Souti Khalil]] 17:49, 1 October 2011 (EST)

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I just uploaded an image to the introduction, if you think its not appropiate or suitable there, feel free to replace it. also, let me know if their is any issue's with the copyright clearance.

--[[User:Z3289829|Souti Khalil]] 17:39, 1 October 2011 (EST)

----

I think that sounds good Rob. I would also like suggest that the last two paragraphs in epidemiology moves to the signs and symptoms section, I think it would fit in a bit nicer there. Thanks Souti, did you want to do something in regards to the 'non-disjunction' sections? I was thinking we should fuse these together into one section (aetiology?), I also added all our non-disjunction pictures into the one section so it doesn't look too repetitive.

--[[User:Z3289066|Elisabeth Karsten]] 13:58, 1 October 2011 (EST)

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Hey Guys, Thanks for the nice feedback :). What I am proposing is that we replace, sorry, the long history paragraphs before the timeline with something similar to what I have written in my last comment. I will not change anything on the main project page without you guys approval first.

--[[User:Z3289991|Robert Klein]] 12:27, 1 October 2011 (EST)

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Hey guys, im also equally sorry for missing the lab on thursday. Rob, are you saying to replace the chunk of text in history with this paragraph and then maybe elaborate more in the timeline?

I'm going to work more on aetiology and history. I noticed that i have only contributed to 2 parts. So apart from looking for images and external links. Is there anything else i can do to help? any other parts you think we should add? Ill definately find a quote to add into the history.

--[[User:Z3289829|Souti Khalil]] 12:16, 1 October 2011 (EST)

----

Added it where?? Do you mean added to the history, or put that instead? Because I think history has more than enough text already. That sounds good though what you've written.

--[[User:Z3289066|Elisabeth Karsten]] 11:27, 1 October 2011 (EST)

Cheers Liz! Also I went through the history and took aboard some of the critical comments that people wrote on our project wall. Leaving the timeline in place, how do you think the history section would look if we added the following:

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; gynecomastia, azoospermia, hyalinised and small testes, absent spermatogenesis, elevated levels of follicle-stimulating hormone (FSH) and hypogonadism. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>.
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient<ref name="PMID17415352"/>. This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref><pubmed> 13632697</pubmed></ref>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome<ref name="PMID3529433"/>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

--[[User:Z3289991|Robert Klein]] 11:17, 1 October 2011 (EST)

----

No worries, looks good thanks rob. Yeh I went through and deleted a big chunk, but it still looks pretty long hey? I'll give that a go, thanks.
--[[User:Z3289066|Elisabeth Karsten]] 09:51, 1 October 2011 (EST)

----

After reading the critique comments, I am proposing that we modify the introduction to something like:

First discovered in 1942, Klinefelter's syndrome is caused by the addition of one or more X chromosome(s) in affected males<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>. He depicted a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis. There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

People were suggesting that our original introduction is too long. What do you all think of this?--[[User:Z3289991|Robert Klein]] 07:19, 1 October 2011 (EST)

----

Everyone,
Firstly forgive my absence from the last lab. It was Jewish New Year so happy new year to all!! Secondly, I will have another look at epidemiology, introduction and glossary and see if I can fix it up according to all the comments listed. I can get this properly done later today.
--[[User:Z3289991|Robert Klein]] 06:14, 1 October 2011 (EST)

----

Hey guys, so we're now able to fix up the page for final submission. If you haven't already gone through the peer assessment, it would be good to do that. From what has been said I've changed the intro around a bit, let me know if I should change it more. I've also fixed up the references so there are no duplications. If you see any, just make sure to fix it up. If you're not sure how to do it I can show you in lab next week, or else just let me know and I can give it a go.

I was also talking to Dona during the lab, and we were thinking that (as was mentioned in the peer assessment) we probably only need one section on Non-disjunction, I know they say different things, but it might be better to combine the sections. I feel they would fit better in aetiology, then maybe the genetics section would fit better in pathogenesis? That was just my opinion really, if you've got any other idea just let us know.

We were also thinking (from looking at the other pages) we should get more interactive things, so diagrams, images, we've probably got enough tables. But a quote or two would look nice, I thought they were a good addition on the other pages. Maybe that would fit nicely into history?

Sorry about the long message, hope it helps and we can get this fixed up. Though I think we've already got a lot of good information. I plan to add a bit to the research section regarding "Future Research", and I'll be looking for more images today.
Good luck!!

--[[User:Z3289066|Elisabeth Karsten]] 12:22, 30 September 2011 (EST)

----

==Peer Review==

A great Effort can been throughout the page. Some of these comments may be helpful.
*Introduction is well researched and referenced but I reckon it’s too long for introducing the topic.
* The History needs to be more organised in a way : like each year should have a separate paragraph. It will make it easier to read.
*Aetiology is well structured, however, I noticed the image needs a reference and a source.
*The Alignment of both images in the Pathogenesis section need to be adjusted to either sides.
* images are missing from the Signs and symptoms. In the table, Puberty and adulthood seem to miss the reference of the source.
* Great work on the table “Other Similar Defects” and the glossary.
* in General, Solid work on the page, references are enough evidence. One Last comment, avoid the repetition of the references(1,3) and some others need to be re-formatted ( 35,36) z3284061

'''Group 3'''

* The introduction is a little text heavy and might need to summarised
* The timeline could be longer
* Image in the Aetiology section is lacking a copyright notice
* The links in Aetiology are good
* An image would be good in Sign and Symptoms
* Pathogenesis needs more referencing
* Some information has been repeated in more than one section
* Links to the Glossary might be useful
* Overall its a good job
--[[User:Z3292953|z3292953]] 11:10, 29 September 2011 (EST)

'''''Klinefelter's Syndrome (Group 3) Peer Review:'''''

Introduction: Information needs to gloss over the entire page a little bit more. Also, the image used has not been referenced correctly and needs to have a copyright notice and the student template.

History: Seems a bit repetitive at first glance. Would it be possible to combine all of this information into the one table? Otherwise, information is good.

Epidemiology: Information is good, however the picture on the left hand side is too small. They have been referenced well.

Aetiology: Picture in this section is slightly ambiguous. Some readers may get confused. Possible more information as to what the picture is portraying. Also, reference the picture and make sure it has a copyright notice.

Pathogenesis: Good information and great hand-drawn images. Possibly need to be slightly larger and explained further. Only 2 references in this whole section?

Signs and Symptoms: Good, succinct list. However, maybe a bit more description? Also, images seem out of place. The images need to have correct referencing format and need to contain the student template. First image is too small.

Diagnosis: Good information. Image needs proper referencing and student template.

Management: Image needs a label at the bottom. Otherwise good image.

Other Similar Defects: This section was well done!

Current Research: Good information but possibly break up the text with a picture or two.
Well done and good luck with editing! --[[User:Z3290808|z3290808]] 10:41, 29 September 2011 (EST)

Klinefelter’s Syndrome – Group 3

* I thought the introduction was very thorough however it didn’t really flow and came across as rather disjunct. Maybe you could actually be a little briefer in this section as it does contain a lot of detail that could possibly serve better in other sections. Good use of image in this section.
* Good use of the table in the history section, maybe an image in this section would look nice also. Use of bullet points as suggested by other reviewers might help to give a more succinct overview, but I thought the writing in this section served well.
* Putting both images in the Epidemiology section on the right side of the page I think would look better, also the sizing looks like they could be matched.
* Aetiology is very well written. Good use of images.
* Some of the pictures need to be referenced correctly and also a little more detail once you click on the images is needed to help explain exactly what is being shown.
* Missing pics in Signs and Symptoms table. Maybe if its hard to find some you could remove this heading from the table and just have the images offset, as then it would not look incomplete.
* Some formatting issues in diagnosis section. I liked the inclusion of the movie clip.
* Current research could be better elaborated. Good explanation of papers however it doesn’t give an overall feel of what is happening in the field. Also the inclusion of future research direction could be an important point.
* Glossary a little incomplete.

--[[User:Z3288196|Z3288196]] 10:39, 29 September 2011 (EST)

'''Peer Review'''
You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

Oh and... YOU DON'T NEED X-CHROMOSOME IN GLOSSARY. The 16yo girl sitting in this lab knows what this means...
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:28, 29 September 2011 (EST)

Group 3:

The long introduction and history needs a pic.

The pictures in epidemiology are really small.

Links to the videos are a good idea.

There is an inconsistent amount of referencing throughout the various sections. Some sections have an excessive amount of referencing and others have just enough. Maybe 2-4 a section.

The references take up quite a bit of the page most probably because there are repeated references that have not yet been addressed.

z3332178 =]

'''Group 3:'''

*intro: the structure of this is a little confusing and it’s not really clear what you’re talking about. The flow of this section is really important – think ‘if I read it on a wiki page, would I read any further, or would I search a different page cos this was just too confusing?’ It might be good to start off your first sentence introducing the disease instead of talking about what happens in normal meiosis first. These few sentences that you put in the middle would be a good few opening sentences.. ‘One of these is known as Klinefelter's syndrome. This describes a syndrome where a person may have one or more extra X chromosomes. This is most commonly due to a process known as non-disjunction during meiosis,’ but start off with ‘Klinefelter’s syndrome is….’ But the content was good.

*history: this section was good with content and structure, but perhaps replace the second paragraph that has all the wordy dates with the timeline and stick your references there. Sometimes it works better with fewer words in a table than a chunky paragraph.

*epidemiology: making the pictures bigger would be nicer. Also theres a lot of info about stuff I would read under clinical manifestations which should be placed there instead.

*etiology: overall good section. The images were really useful. Loved the animation hyperlinks.

*patho: working on the ‘nondisjunction’ to be in one continuous line under the images would be easier to read on the viewer. Other than that, good section.

*signs and symptoms: good section. Easy to read. Concise.

*diagnostics, and the following subheadings: were all easy, well written, flow was good.

*glossary: really liked how you subheaded each part of the alphabet with the letters ‘A’, ‘B’ etc.

--[[User:Z3290558|z3290558]] 09:56, 29 September 2011 (EST)

'''Peer Review'''

:*The first paragraph is not necessary, talk about Klinefelter’s specifically not about sex chromosomes. This can be discussed further in the webpage.
:*Double spacing of paragraphs and other formatting looks awkward.
:*Great historic information but could be integrated into the timeline instead of having large paragraphs and a timeline.
:*Really liked “other similar disorders”. Great idea.
:*Some references need to be fixed so there is not double ups in the reference list.

--[[User:Z3217043|z3217043]] 08:55, 29 September 2011 (EST)

'''Peer Review'''

The wiki has overall interesting information and is well structured. You have also taken all of Mark Hill's suggestions and improved on the site a lot. Some issues:

:*Introduction is a little confusing and not very understood well. Should start off with Klinefelter’s description.

:*Some images are too small. To expand images while reading the wiki breaks up the flow, especially the table images.

:*I don't like the break-up of the alphabet letters in every title on the Glossary section; I find it very distracting.

--[[User:Z3293267|z3293267]] 08:53, 29 September 2011 (EST)

'''Peer Review'''

*Intro: Not a very good idea to introduce the disease with an overly simplified/unexciting image of meiosis, especially if you want the responder to keep reading. I’m sure there something more exciting to represent the disease.

*History: Thorough research, you just have to find a better way of representing it. Take the text, break it down and add it to the timeline. If I was given this to read I would look at the timeline and skip the text, it’s too much.

*Epidemiology: image: “Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png”. The png should not be left at the end of image and quite honestly the table is hard to understand with little explanation given. Wouldn’t people ask what is “ F(1,27= 5.9, p=0.02”? Either explain the table thoroughly or get rid of it.

*Aetiology: Animations were excellent! Perhaps use still-frames as images in this section, because the picture provided is a bit dull and looks very similar to the opening image.

*Pathogenesis: The two images look very similar; perhaps use different colours to indicate their differences. It will make the page more appealing also. The information is relative and easy to follow, although some information is overlapping with aetiology.

*Signs and symptoms: Love the table format- but more information is required. More detail on each section and corresponding images would improve it. Also there is no referencing in the “puberty” section.

*Management:“Action of Amoratase Inhibitors on Production of Estradiol.JPG” is not referenced.

*Other similar defects: It’s a lot more thorough than a few of the sections explaining the disease itself. I don’t think you need to be this descriptive in this section.

*Image/text ratio: need more interesting images (no more cell division images though), and also need to be more detailed in a few sections as mentioned above.

*Overall: Good job, but you still have some work to do.

--[[User:Z3290270|z3290270]] 02:35, 29 September 2011 (EST)

'''Group 3 Peer evaluation'''

*The introduction is good. It brief and informative of what t o expect in the page. The only criticism I have is that the historical background that was placed towards the end of the section, which should probably have been in the beginning or incorporated somewhere there.
*The History section is good, but probably too detailed. I think you can mix the timeline and history together and make this section a bit more concise.
*Epidemiology is a bit of a disappointment for me. There is a bit of information of the demographics of the disease, like prevalence, but I think epidemiology should go deeper into it, like talking about geographical distribution or if there is any race that are more inclined to developing the syndrome. Also this section ended up being an in-depth illustration of a patient’s clinical manifestation. Probably a few statistics on what percentage shows these different types of manifestation and figures some figures of the variation in mutation.
*The etiology section is very informative and I think it has all the information needed for that section. I just think that the arrangement of the information could probably be changed a bit. I think the genetics subsection is unnecessary, even though it does break the section up a bit and allows categorization of it. I just think that you could organise the ideas in this section better than what it already is. The image used here was very appropriate and aids the reader.
*I really like your pathogenesis section. It’s simple yet informative. It is very effective because the terms and concepts that you guys have here are not foreign to the reader because you have already introduced them beforehand, or explained it. Only downfall I guess is the referencing. There is only one section of your information that is referenced.
*Signs and symptoms are done well. You got away with just listing them because most of it is self-explanatory. I guess the only thing that will make this section amazing are some more elaborate images.
*Diagnosis section is done quite well, although the heading should be reconsidered to something like diagnostic test/procedure or something because the diagnosis is “klinefelter’s syndrome”. You also did a good job in incorporating what the tests are looking for, especially in the karyotyping bit. Unfortunately, this was not done for prenatal diagnosis methods, so a bit more information on this one. Finally, I don’t think the statistics need a whole subheading for it. It could just be part of an introduction to this section.
*I like the management section and the image that you used with it is used appropriately and very useful
*The other similar defects is informative, but I think that you went into far too much detail for it in a page dedicated for klinefelter’s syndrome. It is written well and the information in it are amazing though.
*I like the current research section because it says to the reader that the information on this page are up-to-date, giving the whole page credibility. What would probably make it better is a future direction kind of area, where you can put in some proposed theories or studies by researchers, and at the same time some of your own ideas of the direction where this syndrome should head into.
*I am not a big fan of glossaries, but it does look good
--[[User:Z3290841|z3290841]] 10:21, 29 September 2011 (EST)

'''Peer Review Assessment'''
*Overall, good use of sub headings and layout.
*Maybe start the introduction with the actual disease rather explaining the genetics behind it. Got a bit boring. However rest of it was well written.
*History section is well researched. Table is a good summary of the key events. Try and insert an image in this section to break up the heavy text and bring some color into the page.
*The epidemiology section contains information about clinical manifestations and appearances that can be included in a different section. Try and refine this section a little bit. Enlarge the two images in this section.
*Aetiology was well written. It might be a good idea to include some text below the student drawing included in this section explaining it. It doesn't make much sense at the moment.
*I liked the pathogenesis and sign and symptoms sections
*Liked his 'other similar defects' table. Explains the information quite well.
*Very well researched assignment.
--[[User:Z3291622|Z3291622]] 01:23, 29 September 2011 (EST)

'''Peer Review'''
* Picture under "management" is not explained.
* Introduction properly touches on all the topics elucidated later without crossing over too much.
* History is made relevant, linking it to Signs and Symptoms as well as Aetiology.
* Pathogenesis needs more references, as could Signs and Symptoms.
* The layout of Diagnosis At Birth is peculiar.
* Signs and Symptoms could use more demonstrative pictures.
* Glossary is fairly comprehensive.
* Use of related diseases section is interesting, but perhaps should be included within Diagnosis under "Differential diagnoses" or something similar....
--[[User:Z3290689|z3290689]] 00:28, 29 September 2011 (EST)

'''Peer Review for Group 3'''

*The first paragraph of the introduction could be inversed so it can actually start with what Klienfelters syndrome.
*Introduction seems a bit long, making it a bit briefer will capture the audience’s attention better.
*Within the history section the dates should be in bold so that it is easier to follow the information in this section. However, the history does give a good background to the syndrome.
*Table with major advancements is well done
*Epidemiology includes alot of information that doesn’t relate to epidemiological studies, and rather talk about clinical manifestations of people with the syndrome. Maybe put this type of information under another title.
*Figure 4 in the aetiology section should be explained more so that readers could understand what they are looking at.
*The genetics section under the aetiology is interesting, but is it necessary for it to be there, or how does that info link to Klienfelters Syndrome?
*Genetic pathogenesis is explained well. I think the two diagrams should go after the non-disjunction paragraph as it will make the page look better. Also you could talk about how this problem produces the problems for the patients throughout their life.
*Good use of table and dot points in the signs ans symptoms page. It will look good if you have a picture for all categories as you already have 2.
*In the diagnosis section, a little effort should be made to explain how karyotyping occurs as it will make that part better. Other than that the section is good
*I like the ‘other similar defects’ section as it allows the reader to compare and contrast klienfelters with other diseases
*Current research presents a picture to the reader about the current research area for klienfelters.
*Referencing MUST be fixed up as there is repetitive referencing seen in the list.

--[[User:Z3291317|Z3291317]] 23:43, 28 September 2011 (EST)

'''Group 3'''

Introduction: I think you need to explain what the disease is before you explain the genetics behind it. Also, this section seems more like a summary of the whole project. I think you could change it a bit to include more general information on the background of the disease before going into detail.

History: I think this section would be good if all the text was incorporated into the timetable and some pictures added to balance out the text.

Epidemiology: Good section overall however, the pictures could be a lot bigger.

Etiology: Good section but I think the picture needs a caption to explain what the diagram is referring to.

Pathogenesis: This section is clearly explained. The pictures are great but need to be bigger.

Signs and symptoms: The table is good but I think it would look much better if you added pictures for all the sections.

Diagnosis: Similar advice to most other sections- the text is good but I think you should add some pictures to demonstrate some of the abnormalities.

Management: The picture would be good with a caption to explain what the diagram means.

Defects: The table is good but a couple of the pictures are far too small.

Current research: Good section, but again, needs some pictures!
--[[User:Z3291324|z3291324]] 23:20, 28 September 2011 (EST)

Group 3

Hi, overall, a nice project page with interesting information.

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: Nice introduction, good flow and easy to read. However, image needs proper information and perhaps 'This disorder was first described by Harry F.' could be placed earlier on in the intro rather than in the middle
#* History: Nice section, very interesting
#* Epidemiology: First paragraph is good, but I feel the rest of this section doesn't quite belong here, such as the information on seizures, IQs, diagnosis. This section should focus on stats (sex/birth/ethnic/demographic/etc). Fig 2, 3 belong more in the signs and symptoms
#* Etiology: the '1:1000 male' contradicts the '1:500' given in epidemiology. Fig4 needs coyright information
#* Pathogenesis: Needs better referencing, also placing fig 5, 6 on either side doesn't look too good with the text. Perhaps place them below one another?
#* Signs: Seems a bit incomplete, it'll also be good to explain the image of 'pubertal gynecomastia'
#* Diagnosis: Sentence structure could be improved, ie. 'performed because physicians may suspect it because of clinical findings'. Information is interesting, but could be presented more clearly, perhaps in a table?
#* Similar defects: very nice, presented well with good information, easy to read
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Good images used with a nice range of self drawn images. However, lot of the images need to be formatted properly with required information
#Content is correctly cited and referenced.
#* overall referencing was well done, except pathogenesis needs more referencing
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* Nice range of references used
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
#* The information is there, but maybe from now til final assessment, you could do further research in all sections, as they do seem a little short.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* better page layout
* glossary: sorry, but I feel the alphabet subheadings here are not very effective as you have it in alphabetical order anyway

--[[User:Z3291643|z3291643]] 22:01, 28 September 2011 (EST)

'''Group 3:'''

•Good subheading structure, the page flows nicely

•Some parts of the introduction need to be reworded and it should start with an explanation of Klinefelter’s rather than the description of meiosis which is i think is unnecessary at the very beginning of the page.

•Detailed history in the text section, however is the timeline finished? Research after 1970 needs to be completed.

•Glossary needs to be completed, and i’m not sure if you need the separate headings for each letter in the glossary as it spreads it all out a lot.

•Lots of the references are repeated

--[[User:Z3332183|z3332183]] 21:25, 28 September 2011 (EST)

'''Peer Assessment Group 3 Klinefelter's Syndrome'''
*Your introduction is interesting and a good summary of the page
*The history is good however could use a picture
*The images under 'Epidemiology' have quite poor resolution, can hardly read them
*The rest of the page looks great and I have no more to add.
*It is easy to read, well balanced text and pictures and informative
--[[User:Z3308968|Tahmina Lata]] 20:54, 28 September 2011 (EST)

'''Group 3: Peer Assessment'''
* You have constructed an informative page about an interesting syndrome
* At this stage it's a little text heavy, so may be you can cut it down and add some pictures instead
* In the history section it would be great to see these dates from the table with the text blended in, so it's on chronologic flow.
* You seem to take it very serious with the mitosis or not communicating with each other because you have four pictures of mitosis in three different sections. One picture and a good explanation would be sufficient. Then you could use the rest of the space for other pictures.
* The table for signs ad symptoms is great, but looks a bid empty. So may be you can change the format or add some more pictures.
* May be you could write a bid more about therapeutic options. I would find that more important then "similar abnormalities"
* Good referencing through the section. Just change the "double referencing"
* Overall, you page has a lot of information, may be you can balance it a little more out, communicate so you don't have "double" information and a few more pictures would be great.
--z3279511 17:08, 28 September 2011 (EST)

'''GROUP 3 Peer Assessment: Klinefelter's Syndrome'''
*I feel that the introduction is too lengthy, it should be summarised a little more. Although the info is informative, its structure needs some work- grammar and punctuation should be reviewed and sentence structure could be improved
*Figure 1 could use a more descriptive legend
*Historical information is ok, maybe could be improved by extending the timeline to a more resent years, also an image wouldn't hurt, just to break up the text a little
*epidemiology could use some proof reading to correct minor grammar mistakes e.g. "Males born with Klinefelter syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes", sentence structure could also be reviewed so this section flows better (some sentences are short, but other than this, this section is informative
*Incidence is repeated twice, maybe could stick to one section, and it's different in each section (1 in 50 000 or 1 of every 1000 male births?)
*Aetiology (don't really know what this means), and the subheading "genetics" could be a better choice for the whole section, but info here is informative and understandable
*I do like the links made in Aetiology, the picture in this section could use a better legend and needs to be referenced properly (no copyright statement?)
*There is overlapping info in the Aetiology and Pathogenesis sections (both have Non-disjunction as subheading), and both have the same sort of images
*Table in signs and symptoms is too small should be a lot bigger so detail can be seen, it also needs to be referenced properly
*The info for signs and symptoms is good in a table, but it would be better if the table had colour so the reader can distinguish each section of the table
*diagnosis is informative

Overall:
*Reference list needs some work, some of the references have been repeated
*Project could be improved by finalising the glossary and maybe linking the words in the body to the glossary itself
*Images need to be referenced properly and some need more informative legends
*I feel some of the information is a little repetitive, maybe could read through and edit so it flows better
*subheadings and headings could be reviewed and re-organised so page flows better
*I do like the feature of links added throughout, maybe more would make it better

--[[User:Z3331556|z3331556]] 14:28, 28 September 2011 (EST)

'''Group 3 Peer Assessment'''
* Try to link your sentences in general - at times the reading is quite disjunct and difficult to read. Try to rewrite sections and see if it can be written in a more succinct manner.
* In general, keep the images on the right hand side of the page - I know you want to break things up, but if images are kept on the left then it disrupts the paragraph lining and makes the information difficult to track with the eye (just a minor thing, this is my opinion anyway)
* Some subsections just appear too short; is it really necessary to make a subsection for one or two sentences, as is the case of karyotyping? Try to implement all of the information into one paragraph
* The first image requires a proper reference to the work; is there any copyright information? And also protect your hand-drawn images - they are drawn excellently, but have no copyright information (unless you are happy with the images been used straight away by other students! :) )
* The current research section and possible treatment options section is far too brief; if this is a syndrome that causes many problems, then there should be a fair amount describing our direction of research and methods in which we can combat this syndrome. Try to find more information here!
* Overall, a good balance of the images and format, but reconsider the structure of paragraphs and subheadings so that the entire project has a better feel. Many sections feel like they have been started with great enthusiasm, but this has burnt out over time, giving the project a feel that some sections are just left incomplete. Try to fix this!
--[[User:Z3288827|Leonard Tiong]] 09:37, 28 September 2011 (EST)

'''Peer Assessment'''
*The first two paras of the introduction belongs in the genetics/etiology section. Need a broad intro to the actual syndrome and what happens in it. You don’t need to give a brief overview of all the sections, this isn’t an English essay.
*History- break up with bullet points?
*Figure 3 is a bit small – a bigger pic will look better I think
*Pictures in the Pathogenesis section look funny with the text – maybe have one under the other? It just squares the text in the middle and it looks odd.
*Don’t forget the missing pics in the signs and symptoms table
*History/timeline table might look better in purple – keep it consistent with the others.
*In the Current Research section, the 2nd paper that you have described is written with very colloquial language – can’t use that here! Maybe have a brief intro para about current research and where its headed etc, not just a description of papers. Also, maybe link them to other papers, e.g. This paper shows similar results to _______, surely there are similar findings in particular areas of research?
*Fertility picture needs to be in a ‘Figure’ box with a description and explanation of what it means.
--[[User:Z3332824|z3332824]] 23:30, 27 September 2011 (EST)

'''Group 3'''

*I think the introduction should be a little more concise
*History could work better if all the information was summarised in a table/timeline rather than having paragraphs then a timeline. *Also, I find it a little hard to believe that no findings have been made since the 1970s.
*Epidemiology would probably benefit with subheadings
*Signs and symptoms are nicely set out
*I like that you have added a comparison of other diseases
*Maybe add a few more researches from 2011 rather than 2010 (if possible)
*Overall, quite a good project with some minor adjustments needed

Group 3:

*Whilst I appreciate the introduction and its content, I feel an introduction doesn’t need to be of the same size as some of the other sections of the project. It is to give a mere idea of the condition.
*History could be broken apart with dot points or bolded dates instead. How about a picture of Harry Klinefelter?
*Aetiology picture has no link to the article or where it was found, and no copyright notice.
*Pathogenesis has very little references, surely more would have been used.
*Images in table are blank and a lot more references would have been used than shown.
*space out the subheadings so they don’t look disjointed in diagnosis.
* references have not been listed properly (various links for same article)
--[[User:Z3291423|z3291423]] 18:09, 27 September 2011 (EST)

Group 3: Klinefelter’s Syndrome
*overall look: inconsistent formatting, imbalance of text and images in some sections, appropriate headings used.
*introduction: very broad, maybe too much detail?
*history is well researched; I really like the timeline at the end which summarises the major advancements. But it is very short and ends in the 1970s. It could include current research/advancements.
*Epidemiology: could benefit from a few subheadings or breaks in the text.
*Aetiology: I really like the use of external links.
*Signs and symptoms: works well in a table format but not sure why some cells are coloured and others are not.
*Other similar defects: interesting addition to the webpage, allows audience to continue research. Also demonstrates extensive knowledge of the syndrome. Great idea!
*Minor adjustment: just for convenience, glossary terms could be linked
--[[User:Z3332327|z3332327]] 16:14, 27 September 2011 (EST)

'''Group 3 assessment:'''
*Introduction begins in a confusing manner should begin explaining the disorder Klinefelter’s syndrome before explaining the genetic component of meiosis. Where the image was explained though would be more beneficial if the introduction have an image of the founder of the syndrome within this section or within the history heading.
*History has clear structure with explained information of the progress with relation to the timeline of the syndrome, images would have been more useful within this sub heading to make livelier instead or too much text.
*Epidemiology detains the male component though could explain female areas related to syndrome as well figure 3 .
*Pathogenesis is organised with images placed in areas which bring upon confusion where fig 5 and 6 both linking to Non-disjunction, image placement beneath text would be better placement.
*Signs and symptoms could have a little more elaboration and/or more images
*Sub heading of diagnosis at birth needs to place either in the centre or down 1 sentenced to become more organised.
*References should remove any repeats and the links below should be manually added to the references either under another subheading or normally
*Glossary should be linked throughout, either linking the word to the glossary or even bolding the terms so no confusion for people without any background in the area can understand.
z3332250 23:43, 26 September 2011 (EST)

Group 3 Peer Review

*Well structured and organised
*Timeline seems odd that it ends at 1970? If further information cannot be found, try to present this in a different way
*Figure 2 and 3 could perhaps be a little bigger
*Should a copyright statement be included in some of the images?
*Signs and symptoms table is great
*Some duplication of information throughout page-unnecessary
*Video link is a nice extra
*Well balanced text, images, and tables/graphs
*Overall, a well written page and visually appealing
--[[User:Z3308965|Fleur McGregor]] 18:48, 26 September 2011 (EST)

===Comments on Group Project 3===

Group 3

*Introduction seems a bit wayward to begin with. Maybe introduce the syndrome first and then briefly explain meiosis, it just seems a bit indirect. I like how the intro touches on some aspects to be described later in the page but, good work.
*History section could be organised a bit better I think, the combination of text and timeline is good but there must be a balance, right now there’s a big block of text and a teeny timeline
*People might have already said this but I think the epidemiology section is too broad and covers topics outside of its section (clinically diagnosed characteristics and such)
*Aetiology – I definitely like this section, the image is perfect and relates to the non-disjunction paragraph, information provided here is clear and easy to understand.
*Pathogenesis – maybe consider reformatting the images so that the information under ‘Anaphase Lagging’ is easier to read, and the heading ‘Nondisjunctiom’ is not in the middle, would add to continuity and the flow of the entire page if all headings were aligned to one side
*Other Similar Defects – this table is really hard to read, but the information is good, although it does need to be referenced properly
*Nice glossary and current research headings, I don’t really see anything to fix. Good job guys.

--[[User:Z3331469|z3331469]] 06:58, 29 September 2011 (EST)

'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

--Z3389806 07:08, 26 September 2011 (EST)

'''Group 3'''

*Introducton: the beginning is a bit to abrupt, very nice image, otherwise good content

*History: very detailed information, useful timeline

*Epdidemiology: fig.3 would look better on the right side, the content is good

*Aetiology: no copyright information for the image, good use of subheadings.

*Pathodenesis: again, figure would look better on the right side, it disrupts the flow.

*Signs and symptoms: good table, the images look a little lost though, so maybe place them on the right edge, “age and intellect” could be bigger.

*Diagnosis: well done

*Management: good content, nice flow

*Similar defects: good content, but the structure could be better, maybe place the content in a table without the dots. Everything that belongs to e.g XO should start at the same hight

*Research: interesting section, well done

*Glossary: seems incomplete

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 12:13, 25 September 2011 (EST)

Group 3
* The first thing I noticed is that the project is very text heavy. Also- there are 4 images of mitosis. Is this really necessary? One is enough and you can use the other spaces to put other images in
* The introduction gives a nice, broad overview of the project. I understand immediately what is going to be said. But is there not an image of a patient to put here to draw the reader in? Maybe its just me that isn’t very excited about images of mitosis sorry.
* The history section would work better as a list of dates and names rather than a bulk of text
* Has there been no research since the 1970s? More recent findings need to be added to the history
* The epidemiology is very interesting- but there is a lot of clinical manifestations here that are described later. There is a double up in information.
* Signs and symptoms works well in a table- but more images of the condition would make it even better
* The comparison of other conditions is excellent! Great idea.
* Your information is there is just needs to be organised a little better and the fact that you have double ups on information and pictures indicates that there may not be any communication in the team- either that or laziness to find a different picture. Look forward to seeing your final project!

'''Group 3'''
* Good over all structure with the use of headings and sub headings. A very interesting syndrome and the page is easy to read.
* I think the intro could be condensed a little, as it should get straight to the point.
* I enjoyed reading the history section and good use of table and summary of history.
* I like figure 1, very nice that it was done by a student!
* figure 4 Maternal Non-Disjunction.. Is this a student drawn pic or did you use it from somewhere.. a little unclear.
* I was nice to see sign and symptoms tabulated, which made this section very easy to read and understand. good use of picture here. Could you find anymore relating to the signs and symptoms?
* I liked the addition of a movie link.
* The sub heading of diagnosis were very appropriate.
* Other Similar Defects- very interesting to add this in..
* Interesting current research: nice that it has been summarised.
* Make sure your reference list hasn't doubled up.
* Just for clarity it might be nice to use the same colour table throughout the page.
* It was good to see some of your pictures correctly labelled.

*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?
The genetics part is good though.
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.
*'''Management''': Looks good.
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.

'''Peer Assessment: Group Project 3'''
*The introduction is informative, however I think that the small paragraphs at the end detract from the section as a whole. It would be better to integrate these more so that they flow on from the previous text.
*The history section provides both detailed information and a timeline, which makes the historical stages easy to comprehend and refer back to.
*Is the image in the section on aetiology drawn by a student? If not, then copyright information and referencing needs to be included.
*In the section on diagnostic procedures, the image could be placed on the right for ease of reading.
*The figure in the signs and symptoms section and the figures in the epidemiology section are too small.
*Using colour borders in the signs and symptoms table would make it a bit clearer.
*The links to animations and a movie are great uses of additional material.
*Under the information in some of the images you have uploaded, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*The references should not be duplicated and can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
--[[User:Z3217345|z3217345]] 13:28, 27 September 2011 (EST)

'''Group 3 Assessment'''
*The Meiotic Non-disjunction jpg doesn’t have the proper citing or information about future referencing abilities.
*In the history section, I like how the occurances are both described in detail and set forth in an easy to read table format. Very organized.
*In the Aetiology section, where is the referencing for the Non-disjunction videos? Is video copyrighted?
*The Aetiology section and Pathogenesis sections seem to contain almost identical information. Are both necessary, or could they be combined/ one deleted?
*If you decide to keep the Non-disjunction videos, are the pictures in the Pathogenesis section necessary? Or do they just become redundant?
*In the Epidemiology section, both pictures need to be enlarged; they are so small I can’t make a distinction as to what’s on them.
*Signs and Symptoms- This section overall looks very good as far as information goes. The only thing I would suggest is to separate the different age sections a little bit more; their symptoms look to be running together from group to group. Also, try increasing the picture sizes, as they (especially the first one) is difficult to read.
*Again, for the video under Karyotyping, where is the referencing and copyright information on this?
*Action of Amoratase picture- This still needs to have the disclosure statement reguarding re-use and copyright guidelines. Also needs a descriptor sentence below the picture.
*Glossary- Shouldn’t there be references for these definitions?
*Both the Similar Defects and Research sections seem decent. Only suggestions:

-Similar defects chart: Try bigger pictures and sentences of less length.

-Research- Try adding a picture to the section to make it more aesthetically appealing
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
--[[User:Z3391078|Ashley Smith]] 14:00, 27 September 2011 (EST)

'''Group 3:'''
* The introduction is very lengthy, some parts feel as though they would be more appropriate in other sections. The image here fits nicely with the text but it could benefit from a more descriptive legend and needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>.
* In the history, you begin to use the short hand “KS” without an initially stating that this is the abbreviation for “Klinefelters syndrome (KS)”. The dates that are mentioned are very detailed although it ends in 1970, were there any other breakthroughs since then? A picture of Klinefelter would be a nice touch here.
* Epidemiology requires some proof reading as there are a couple of little mistakes and the images would have more of an impact if they were slightly larger.
* I like how you have linked figure 1 to the non-disjunction sub-heading under aetiology. The image in this section could benefit from a coloured legend, ie. Instead of saying “Blue circles are male cells”, in a box include an actual blue circle = male cells along with the other descriptions. It also needs to be properly cited.
* There is too much repetition between pathogenesis and aetiology, maybe discussion between these two students is needed to minimise repetition. Good hand drawn images but you need to include the student template as mentioned previously.
* Signs and symptoms would look better in a coloured table and with more images. I don’t think it is necessary to repeat the image comparing age and intellect here.
* Diagnosis; nice use of another form of media – a video. The abbreviation of KS in this section needs to be established first by placing KS after the first time you mention Klinefelters syndrome.
* Management is very concise and thorough
* Other similar defects; nice touch, it could look more appealing with the use of colour and larger images though.
* Current research is formatted nicely and flows well

'''Group 3 - Peer assessment'''

*The introduction is abit lengthy and choppy because some paragraphs are just 1-2 sentences. Maybe try to connect them into one paragraph and try to make it flow better.
*The history was quite informative maybe put the timeline at the top and the text at the bottom and maybe try to add more recent dates.
*Epidemiology - the use of figures are good and it is explained well in the text
*Aetiology - good idea in external linking images! the information is easy to easy as it is well structured
*Signs and Symptoms - the table is abit confusing to read, althought the information is well reduced
*Other Similar Defects - maybe the use of lines within the table would be better to separate the columns and rows because it is abit hard to read

--[[User:Z3330313|z3330313]] 19:50, 28 September 2011 (EST)

--z3290815 15:54, 28 September 2011 (EST)

'''Peer Review'''

* a lot of writing and so makes the wikipage interesting to read
* the image in the pathogenesis section needs fixing
* the image layout is not organised well
* needed to explain Klinefelter's disorder in simple terms. I could understand it but if it was explained in a more simple way it would be much better.

--[[User:Z3060621|z3060621]] 20:58, 28 September 2011 (EST)

'''Group 3'''
'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are present.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Under aetiology, it might be good to add a sentence or two about the cause of Klinefelter's Syndrome rather than just jump right into aneuploidy. I understand that it is the aetoilogical agent in Klinfelter's but indicating it as a cause would be good to kinda give the reader a 'flag'. It is not necessary to add the information about aneuploidy in the introduction as i think you could move that section down to a more appropriate part. If need be, just mention aneuploidy as a cause in the introduction rather than dedicate the first paragraph to it in the intro.

'''*Content is correctly cited and referenced.'''
Maternal Non-Disjunction.PNG needs some references, Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG, Pubertal gynecomastia.jpg, Immunoglobulin levels in 15 girls with Turner Syndrome.png and Karyogram of male with 47, XYY Syndrome.png needs to be correctly referenced. duplication of references need to be fixed. More references need to be included when there is a huge chunk of text or it looks very much like you got everything from one source only.

'''*The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.'''
Good drawings - explanations are understandable.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
There is a significant reference list but not enough in-text referencing.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
A lot of content on genetic problems, maybe put something in about development of embryo (if applicable)?

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has shown development and editing to be based on the above guidelines although some smaller details could be fixed.

--z3329495 21:11, 28 September 2011 (EST)

==Discussion==

----

Hey i have been looking for a profile pic for some time and none have come up. So prob better if you don't look for it because I am afraid that you will waste time. Nice! birthday cake :) I should do that for my dad's bday which is coming up.
Anyways see you tomorrow
--[[User:Z3289301|Dona Cho]] 23:55, 21 September 2011 (EST)

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Hey Dona, thats a good idea! i like all the pics that you have added, and pathogenesis looks good! I just baked my dad a birthday cake and planning on doing some work on this now. So i will probably be up for a while. I am also looking for pics of H. Klinefelter. Good work!--[[User:Z3289829|Souti Khalil]] 21:12, 21 September 2011 (EST)
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I am looking for a profile picture of Mr Klinefelter. I think it will be good to put one in in the introduction section. I am having trouble finding any - but you do come across one pls put one up -I think it will look great!
--[[User:Z3289301|Dona Cho]] 20:19, 21 September 2011 (EST)

----

Guys I thought that it would look good if all the images were order 'figure 1, figure2...'
Just so that it all looks uniform
Hope your ok with it but if you don't like it you can just change it back.

--[[User:Z3289301|Dona Cho]] 17:52, 21 September 2011 (EST) :)

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That looks interesting, but I'm not really up to adding any of that tonight. Feel free to add whatever you like.
--[[User:Z3289066|Elisabeth Karsten]] 22:57, 14 September 2011 (EST)

Hi guys ;)

I was just reading some stuff - found some interesting info related to management (I think it is liz?)

The part of the review is as follows:

'Decreased energy and libido, which are associated with postpubertal testosterone deficit, improve with hormone therapy and often are accompanied by improved confidence and sense of well-being.Androgen therapy should be started when there is direct laboratory evidence of a testosterone deficit or when hypergonadotrophism, which suggests such a deficit, is present. This may occur by the time the patient begins middle school...

Because gynecomastia predisposes men to breast cancer—the frequency of breast cancer is 20 to 50 times greater than in men who do not have Klinefelter syndrome1,2—monthly breast self-examination should be encouraged. If necessary for cosmetic reasons, gynecomastia may be treated surgically.'

The review also mentioned something about 'cryopreservation' so that the precious sperm can be stored and used for later IVF.

If the above sound interesting, it might be good reading the review article (particularly the management section. Follow the link below for the review.

http://www.aafp.org/afp/2005/1201/p2259.pdf

ps. I dont think I will be sleeping much tonight!!

--[[User:Z3289301|Dona Cho]] 22:32, 14 September 2011 (EST)

----

I don't think we can use those pictures, unfortunately. Safest to stick with papers and hand-drawn I think. The timeline looks really really good. If anything, I would be inclined to put a bit less info in the main bit of history and focus on that time line. I think it's a nice visual respresentation of the information.
--[[User:Z3289066|Elisabeth Karsten]] 21:17, 14 September 2011 (EST)

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I found this website which has alot of picture's of KS, and there are only a few copyright statements, can we use them? [http://carregwenimages.com/klinefelters-syndrome-pictures]

Haha, I just saw them! thanks for that! I just edited the history and the timeline. Is the information in the timeline just repetitive of what i have written, should i just remove it? --[[User:Z3289829|Souti Khalil]] 20:09, 14 September 2011 (EST)
----

It did end up happy in the end lol. Yeh they look really good. We're allowed to add links to our page, so I think that'd be best. I'll put those on now. Thanks!
--[[User:Z3289066|Elisabeth Karsten]] 18:46, 14 September 2011 (EST)

Thanks for fixing up the table in signs and symptoms, it looks great!

That video was mean, i was eating when i watched it and i felt so sorry for the little boy, i couldnt watch the rest. :(

If you think we need an animation i found these two websites, but i have no idea of how we would put them on to our page.

[[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm]]
[[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm]]
--[[User:Z3289829|Souti Khalil]] 18:09, 14 September 2011 (EST)

----

That video is so funny! I was laughing to the point of tears while watching this! I don't think Dr. Hill would be too happy if we added the video to our webpage though. Great job Liz once again with the editing. Keep up the good work!--[[User:Z3289991|Robert Klein]] 15:22, 14 September 2011 (EST)

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Hey everyone, I just uploaded our 1 Wikipedia image. It's the karyotype of Klinefelter's syndrome. If anyone founds anything better on Wiki, just make sure you say something and take that one off.
--[[User:Z3289066|Elisabeth Karsten]] 09:52, 14 September 2011 (EST)

So I found this video, it's super cute and lame. But I think it's a nice representation? Not sure how applicable it is though... http://www.youtube.com/watch?v=6q2JxMDaNys
--[[User:Z3289066|Elisabeth Karsten]] 10:08, 14 September 2011 (EST)
----

[[File: Signs and Symptoms by Age Group.PNG|right|300px| Signs and Symptoms by Age Group.PNG|thumb]]

Thanks Liz! I really loved the intro and the picture that you created! Maybe we don’t have to remove it, however I will also be on the lookout for a picture which may better suit the introduction. In the meantime, I was thinking maybe we should order the subsections better, for example; Introduction, History, Epidemiology, Aetiology, Pathogenesis, Signs and symptoms, diagnosis, management, other similar defects and then current research. I just think we should explain the cause and pathogenesis of the disease before the signs and symptoms and diagnosis.

Lastly, I found a table on a website and have created a similar one on signs and symptoms. I'll just upload it here, and we can decide if we want to use it.

That is all. --[[User:Z3289829|Souti Khalil]] 13:13, 12 September 2011 (EST)

That table looks really really good, though it could be easier if we upload it like the other table I put up, as opposed to a picture. I'm happy to do that if you like. And yeh that order looks good too, I'll change it now and if anyone disagrees they can change it back. --[[User:Z3289066|Elisabeth Karsten]] 22:29, 12 September 2011 (EST)
----

Our page is starting to looking really good!! I just fixed up the aetiology, it may need more work to be done though. Liz the picture i made, is really similar to the one you have in the introduction, is it too much?? Sorry about the delay in uploading it. --[[User:Z3289829|Souti Khalil]] 00:50, 12 September 2011 (EST)

That's fine, I kind of expected that. You use it since it fits in with your topic and I'll do another one for the intro. Aetiology looks really good, nice work!

--[[User:Z3289066|Elisabeth Karsten]] 09:07, 12 September 2011 (EST)

----
Hey Liz, Great job with the editing! It looks really good. I will keep on the lookout for gathering more information. --[[User:Z3289991|Robert Klein]] 20:31, 11 September 2011 (EST)

----

Hey everyone, I've just fiddled with the formatting of the page a bit. If you don't like it, of course feel free to change. I also changed the formatting of the table t make it a bit clearer to read, if you preferred the old one though I've saved a copy of it so just let me know. Just looking at the page, some things in epidemiology I think would fit a bit better in signs and symptoms; and eitiology and pathogenesis are a little repetive of each other which I guess we should of expected. But we'll be able to discuss it properly on this coming thursday.

--[[User:Z3289066|Elisabeth Karsten]] 20:24, 11 September 2011 (EST)

To help out a bit, I found some links to articles that are 'Open Access'. This should save time for you guys:
http://www.springerlink.com/content/g68408vq74752421/fulltext.pdf
http://psy.hull.ac.uk/Staff/t.jellema/VantWout_PlosONE.pdf
http://www.autismresearchcentre.com/docs/papers/2011_BCetal_Plos%20biology_unsolvedmystery.pdf
http://www.ojrd.com/content/pdf/1750-1172-5-15.pdf
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020292
http://www.hogrefe.nl/fileadmin/user_upload/Documenten/PDF/Wetenschappelijk_onderzoek/Bruining_et_al_-_Dissecting_clinical_heterogeneity_of_ASD_through_genotypes.pdf
http://www.ijponline.net/content/36/1/36

Hope this helps!--[[User:Z3289991|Robert Klein]] 12:23, 9 September 2011 (EST)

Looks good, thanks rob.

--[[User:Z3289066|Elisabeth Karsten]] 20:24, 11 September 2011 (EST)

----

I had to remove the photo from 'signs and symptoms so that I can confirm it's copyright restrictions. Sorry about that. --[[User:Z3289991|Robert Klein]] 07:44, 9 September 2011 (EST)

----

I edited the Epidemiology and fixed it up as best I could. As well, I found and added a picture to the signs and symptoms section to make it a little clearer. I still seem to be having difficulties with formatting. If anyone comes across charts that I can use for Epidemiology, that would be much appreciated. I still can't find anything that I can use. I will fix up the 'other similar defects' section and have it ready very soon. --[[User:Z3289991|Robert Klein]] 06:39, 9 September 2011 (EST)

----

Hey guys, sorry I've been a bit MIA recently. But yeh I agree totally, I was planning to finish off the intro once everything else is finished, but for the moment I'll make sure I'll finish off my other sections.
And yeh you're ideas re:tables and diagrams sounds great. I'll have a go at drawing a couple on paint as well
--[[User:Z3289066|Elisabeth Karsten]] 21:39, 8 September 2011 (EST)

----
Good idea Souti! As well as that, I will retype my sections and try and fix them according to what Dr.Hill wishes. Maybe for treatments, you could speak about the drugs used to manage the condition. We do need to edit the other sections and add much more content and diagrams. Perhaps a few handrawn diagrams wouldn't go astray?--[[User:Z3289991|Robert Klein]] 18:40, 8 September 2011 (EST)

----
Hey guys, I noticed earlier today that Mark Hill has put comments on our page that we need to change and improve. So i'm going to take out 'case study', and replace it with 'treatments'. What do you guys think? Make sure you have a look at what he has said.
--[[User:Z3289829|Souti Khalil]] 17:44, 8 September 2011 (EST)

----

Rob, 'Other Similar Defects' is looking great! I am committing the next couple of hours to Klinefelter's syndrome. Do you guys think we could elaborate a bit more in the introduction, just to give a larger scope of our disease?

--[[User:Z3289829|Souti Khalil]] 11:48, 8 September 2011 (EST)

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I added images to 'Other Similar Defects'--[[User:Z3289991|Robert Klein]] 07:55, 7 September 2011 (EST)

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I have constructed a table for Other similar defects! I think that it should be alright, however there may not be enough info so the conditions may not properly be explained. We are still waiting on a table for signs and symptoms as well as a diagram for pathogenesis--[[User:Z3289991|Robert Klein]] 10:01, 6 September 2011 (EST)

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What we should do is add a table to 'similar defects', a diagram for pathogenesis, a and a table for signs and symptoms--[[User:Z3289991|Robert Klein]] 12:49, 1 September 2011 (EST)

----

Glossary, Epidemiology and Similar defects have all been added. Let me know if anything else needs to be done!--[[User:Z3289991|Robert Klein]] 06:04, 1 September 2011 (EST)

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Alright Everyone,
For the different genotypes dotpoint, I will cover that when I complete the section to do with 'similar defects'. I have fixed up the referencing system. --[[User:Z3289991|Robert Klein]] 13:53, 27 August 2011 (EST)

----

Hey guys,
I have included a list of things that Mark Hill emphasised in regards to our group project in the lab today;

- Different genotypes

- Animal models

- Review articles

- Importance of how the disease comes about (pathogenesis).

So, by next Thursday our main page should have plenty of content under each subheading. 
--[[User:Z3289829|Souti Khalil]] 14:14, 25 August 2011 (EST)

----

Hey Guys,
I have added a discussion tab for any enquires and updates on the progress of our assessment, as well as a referencing tab (or whatever they are actually called) at the bottom of the page. So for each section, if anyone finds relevant articles/images etc. they can place it there.
Oh, and please remember to add new content to the top.
--[[User:Z3289829|Souti Khalil]] 00:53, 18 August 2011 (EST)

----

Hey Guys,
Sorry to be a bother. I am having trouble referemcing properly in the Wiki format, as what can be seen in my Epidemiology piece and also my messing up of the reference list. Would one of you mind showing me how to fix this problem? Thanks so much and I will have the piece on 'other similar defects' prepared by Saturday. The glossary will be uploaded on Monday.
--[[User:Z3289991|Robert Klein]] 05:40, 18 August 2011 (EST)

----

'''Referencing'''
PMID is the reference number that you need

without the ':' will act as an link to the article
--[[User:Z3289301|Dona Cho]] 12:51, 25 August 2011 (EST)

==References==

If you find any good papers relating to someone elses topic, you can put them under these subheadings to help out.

Hey guys! this is a publication which seem to be pretty good!!

http://www.nichd.nih.gov/publications/pubs/klinefelter.cfm
--[[User:Z3289301|Dona Cho]] 12:54, 25 August 2011 (EST)

===Description/Introduction===

===History===

Natural history of seminiferous tubule degeneration in Klinefelter syndrome<ref><pubmed>16172111</pubmed></ref>

===Signs and Symptoms===

===Epidemiology===

Abramsky L, Chapple J.47, XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn. 1997;17:363–368.

Bojesen A, Juul S, Gravholt CH.Prenatal and postnatal prevalence of Klinefelter syndrome: anational registry study. J Clin Endocrinol Metab. 2003;88:622–626

[http://www.aafp.org/afp/2005/1201/p2259.pdf Klinefelter Syndrome]

===Diagnosis===

Hey guys, it's Dona. I put my name down for this section. I will try to get mine done by the end of this week. :)

--[[User:Z3289301|Dona Cho]] 17:23, 24 August 2011 (EST)

===Treatment===

===Etiology===

===Pathogenesis===

===Case Study===

===Similar Defects===

===Current Research===
http://www.ncbi.nlm.nih.gov/pubmed/7446531
Check this out!!--[[User:Z3289991|Robert Klein]] 05:03, 1 September 2011 (EST)

<ref><pubmed>21342258</pubmed></ref>

===References===
<references/>

==Pictures==
[[File:Magnetic Resonance of Head MRI from patient with Down Syndrome and Klinefelter's Syndrome.jpg|thumb|Magnetic Resonance of Head MRI from patient with Down Syndrome and Klinefelter's Syndrome]]

--[[User:Z3289829|Souti Khalil]] 23:57, 17 August 2011 (EST)

[[File:Klinefelter's Syndrome.jpg|thumb|center|Klinefelter's Syndrome]]

--[[User:Z3289066|Elisabeth Karsten]] 23:31, 13 August 2011 (EST)

[[File:Overview of human testicular sample from a patient with Klinefelter's syndrome.png|thumb|center|Klinefelter's Syndrome patient testicular sample]]

--[[User:Z3289991|Robert Klein]] 10:17, 16 August 2011 (EST)

[[File:Kleinfelter syndrome.jpg|thumb|center|Facial dysmorphic features in a child with double aneuploidy—Down syndrome and Klinefelter syndrome]]

--[[User:Z3289301|Dona Cho]] 20:35, 17 August 2011 (EST)

==Topic Choice==

Hey guys, so after having a look at that list I quite like the sound of
*Anencephaly or
*Klinefelter's syndrome

There's loads of resources for Klinefelter's syndrome, but I think Anencephaly sounds really interesting. It's a type of neural tube defect, so we may even be able to do that as a topic - neural tube defects (it's on the list as well).
Just let us know what you think, thanks guys!

I've just attached a review for each

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

[http://www.ncbi.nlm.nih.gov/pubmed/21110233 Neural Tube Defects] or [http://www.ncbi.nlm.nih.gov/pubmed/17089587 Anencephaly]

--[[User:Z3289066|z3289066]] 09:32, 6 August 2011 (EST)

Hey Everyone,
I am leaning towards Klinefelter syndrome as it seemed interesting to learn about. I found a couple of articles on the internet which explore more the epidemiology of the condition amongst the population. Liz, I read through your artiles and they were quite interesting in the way that they explored the genetics behind the condition. We will be able to perhaps link these in with the epidemiology to make our argument more convincing.

Below is a review article:

[http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/(SICI)1097-0223(199909)19:9%3C808::AID-PD637%3E3.0.CO;2-B/pdf]

The Research Article:

[http://jcem.endojournals.org/content/88/2/622.full.pdf+html]

Both articles explore more the epidemiology of klinefelter's syndrome as I felt that it would be interesting to look at its prevalence, and frequency of distribution within a population. The first review article that I hasve linked to explores the frequency of Klinefelter's syndrome in a population along with various other genetic anomalies.

--[[User:Z3289991|z3289991]] 07:02, 9 August 2011 (EST)

Yeh that sounds good to me, if anyone has any objections just let us know. We can figure out exactly what we want in the page on thursday, but yeh should def's talk about the epidemiology.

--[[User:Z3289066|z3289066]] 14:53, 9 August 2011 (EST)

Hey guys!

I think that Klinefelter's syndrome is definitely an interesting disease and it has lots of resources. I think we still need a plan B though, a few other diseases which I thought were really interesting are;
- Thalassaemia
- Anencephaly (good pick Liz!)
- Spina Bifida
I found a really good review article on Klinefelter’s syndrome, although it’s pretty dated.
[http://archinte.ama-assn.org.wwwproxy0.library.unsw.edu.au/cgi/content/full/158/12/1309]
[http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/ajmg.b.30163/pdf]

I shall see you all thursday!

--[[User:Z3289829|z3289829]] 22:15, 9 August 2011 (EST)

Hey guys, this is dona - I guess I am the last one to write on the board (sorry!)

I personally like the topic; neural tube defects. Reasons are 1. there is so much information because it is an umbrella term that includes many conditions like spina bifida and anencephaly
and 2. we will be learning the developing of the neural tube next week in lecture - so it will not be difficult to understand the etiology of neural tube defects

Here are the links:

review article [http://www.ncbi.nlm.nih.gov/pubmed/10899792]

research article [http://www.tandfonline.com.wwwproxy0.library.unsw.edu.au/doi/pdf/10.1080/19485565.1991.9988793]

p.s Hey could everyone identify themself by writing their name before writing on this discussion forum, that way people know whose talking. (please)

--[[User:Z3289301|Z3289301]] 17:23, 10 August 2011 (EST)

===Sections===

*Description/Introduction - Liz
*History - Souti
*Signs and Symptoms - Dona
*Epidemiology - Rob
*Treatment - Liz
*Eitology - Souti
*Pathogenesis - Dona
*Similar defects - Rob

I was thinking it'd be good to also do a topic on recent research, I'm happy to do that one, and should also do a glossary. So we should have someone finalise that, but it'd be really helpful if everyone could just add words in they think would be good as you go. Does anyone want to volunteer for editing that? Just put your name in the spot below so everyone knows.

*Recent research - Liz
*Glossary - Rob
*Diagnosis - Dona
*Case Study - Souti

--[[User:Z3289066|Elisabeth Karsten]] 12:15, 13 August 2011 (EST)

----

Hey Guys,
I have uploaded an image to the Epidemiology section of the Group webpage, however it appears to have distorted the whole webpage in that all the other categories below epidemiology have been pushed to the side. Also, I am having trouble trying to enlarge the image. Do you know how I can fix this problem? The table was referenced appropriately.
Cheers

--[[User:Z3289991|z3289991]] 10:14, 13 August 2011 (EST)

Hey, yeh that should be fine for the moment, don't worry too much about the formatting. You can fix it, but it'll be easier to do once there's text there too move around it.
There should be a page explaining all the details about picture formatting, but I can't qutie remember how to do it off the top of my head. Is that the size of the original image? Because that could be part of the problem.

--[[User:Z3289066|Elisabeth Karsten]] 12:09, 13 August 2011 (EST)

Oh I've just realised what's happened, see how you've put the file name then "thumb"? The default for thumb is to make it slightly smaller and move to the right where it will wrap around whatever text is there. You can try [File name|thumb|left|name] if you want it on the left, or else instead of 'left' you can say 'center'. But it's gotta be 'center', not 'centre' (I think). Or else you don't have to use thumb at all, and just leave it out completely.

Hope this helps.

--[[User:Z3289066|Elisabeth Karsten]] 14:02, 13 August 2011 (EST)

Thanks Liz,
You know what? I will add some text during next week and then play around with the formatting. You are right in your first comment, because that way I can format the picture and text properly. Thanks so much for your help though.
--[[User:Z3289991|Robert Klein]] 15:21, 13 August 2011 (EST)

----
==Peer Assessments==

* Great amount of depth, you have covered each subheading quite well
* It was great to see a comparison to other similar defects
* Non-disjunction is discussed twice, can it be summarised into just the one section?
* In the signs and symptoms section, the images seem to be arranged in a disorderly fashion, maybe place them elsewhere. Also your image comparing age and intellect is extremely small. The sizing of a larger majority of your photos needs to b adjusted
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* There were only two examples of management strategies, are there anymore out there? Maybe you could do a comparisons table for this section
--[[User:Z3332629|z3332629]] 15:23, 22 September 2011 (EST)

2011 Group Project 3

2011-10-07T02:58:04Z

Z3289066: /* Related Links */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Related Links==

'''Internal'''

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

'''External'''

[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | [http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet]

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

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='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Related Links==

'''External'''

[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | [http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet]

'''Internal'''

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
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{{2011Projects}}

Talk:2011 Group Project 3

2011-10-07T02:54:52Z

Z3289066: /* Discussion */

[[2011_Group_Project_3|'''Group 3''']]: [[User:z3289066]] | [[User:z3289301]] | [[User:z3289829]] | [[User:z3289991]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_3_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_3_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Discussion==

Oh did he? I didn't realise. It can't hurt to change it. Ok no worries.

--[[User:Z3289066|Elisabeth Karsten]] 13:54, 7 October 2011 (EST)

Thanks a lot Liz! i'm currently at uni and i will be working on this tonight and during the weekend. Also, i noticed that you tweaked the links section, do you think Mark Hill will mind if we do it this way, as he did specify to have a section called 'Related Links'. --[[User:Z3289829|Souti Khalil]] 13:00, 7 October 2011 (EST)

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Pathophysiology -

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/21655260 This ones about the psychophysiology of having an additional X chromosome

http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1651-2227.2011.02246.x/pdf That's about the generally clinical features, with reference to pathology. It's got some good images, so I've requested permission for their use

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20014371 This one assess the differences of cognitive function of XXY and YYX patients - not sure it would be overly useful though

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20014369 Impact of XXY on cognitive function

I'll let you know if I find anything else

--[[User:Z3289066|Elisabeth Karsten]] 11:35, 7 October 2011 (EST)

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Haha, Dona can you see this?? Robert, Liz and I were talkingabout our group page and we thought that it may be better if we collate aetiology and pathogenesis, so there is no repetition. and then maybe add a pathophysiology section. I dont mind working on it. What do you think Dona?--[[User:Z3289829|Souti Khalil]] 12:10, 6 October 2011 (EST)

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Okay, so the page has undergone some reformatting. Hopefully this will look better, as Souti and Liz have been reorganising the content.--[[User:Z3289991|Robert Klein]] 11:30, 6 October 2011 (EST)

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Sounds good!! i will definately elaborate more in genetics and hopefull find an image to put there.
--[[User:Z3289829|Souti Khalil]] 10:25, 6 October 2011 (EST)

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I think that non-disjunction and genetics should be aetiology instead of pathogenesis. However Souti, you need to elaborate slightly more on the genetics.
--[[User:Z3289991|Robert Klein]] 10:23, 6 October 2011 (EST)

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Thanks Guys! The necessary changes to the Epidemiology have been made. See you all tomorow
--[[User:Z3289991|Robert Klein]] 15:55, 5 October 2011 (EST)

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Hey Liz, thanks, I think the history section is just about complete. I took into consideration all the peer reviews and changed a few things, however let me know if you think anything else needs to be done there. Epidemiology looks good rob!! Also, the picture in the introduction was just something that i found, but if you find a better image feel free to change it. I'll try to work on non-disjunction and aetiology later tonight. See you all tomorrow!

--[[User:Z3289829|Souti Khalil]] 13:49, 5 October 2011 (EST)

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That looks really good rob, nice work. The picture in the intro is nice, but it doesn't have a reference and we do already have an image of the Klinefelter karyotype in the Diagnosis section. I'll see if I can find something else for the intro. The timeline for history looks really good.

--[[User:Z3289066|Elisabeth Karsten]] 13:24, 5 October 2011 (EST)

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Hey Guys,
I tried to play around with an idea for epidemiology. Below is my idea. Note: I have changed nothing from Epidemiology on the main project page yet.

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]
One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.
A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.
Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.
[[File:Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png|thumb|left|Figure 3. The average intellect of boys with Klinefelter's Syndrome differs from that of normal males]]

--[[User:Z3289991|Robert Klein]] 13:40, 2 October 2011 (EST)

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I have amended the mistake in the reference list (6) since there was a citation error. There was a mistake in the original coding. --[[User:Z3289991|Robert Klein]] 13:20, 2 October 2011 (EST)

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Okay, the apropriate changes have been made to the history. I have saved the original copy on my computer of the history for future reference.--[[User:Z3289991|Robert Klein]] 07:36, 2 October 2011 (EST)

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I just got an email from Dr. Mark Hill, he prefers images from journal articles, so he'll probably remove them :( --[[User:Z3289829|Souti Khalil]] 23:17, 1 October 2011 (EST)

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2 images now, feel free to play around with them. --[[User:Z3289829|Souti Khalil]] 17:49, 1 October 2011 (EST)

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I just uploaded an image to the introduction, if you think its not appropiate or suitable there, feel free to replace it. also, let me know if their is any issue's with the copyright clearance.

--[[User:Z3289829|Souti Khalil]] 17:39, 1 October 2011 (EST)

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I think that sounds good Rob. I would also like suggest that the last two paragraphs in epidemiology moves to the signs and symptoms section, I think it would fit in a bit nicer there. Thanks Souti, did you want to do something in regards to the 'non-disjunction' sections? I was thinking we should fuse these together into one section (aetiology?), I also added all our non-disjunction pictures into the one section so it doesn't look too repetitive.

--[[User:Z3289066|Elisabeth Karsten]] 13:58, 1 October 2011 (EST)

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Hey Guys, Thanks for the nice feedback :). What I am proposing is that we replace, sorry, the long history paragraphs before the timeline with something similar to what I have written in my last comment. I will not change anything on the main project page without you guys approval first.

--[[User:Z3289991|Robert Klein]] 12:27, 1 October 2011 (EST)

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Hey guys, im also equally sorry for missing the lab on thursday. Rob, are you saying to replace the chunk of text in history with this paragraph and then maybe elaborate more in the timeline?

I'm going to work more on aetiology and history. I noticed that i have only contributed to 2 parts. So apart from looking for images and external links. Is there anything else i can do to help? any other parts you think we should add? Ill definately find a quote to add into the history.

--[[User:Z3289829|Souti Khalil]] 12:16, 1 October 2011 (EST)

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Added it where?? Do you mean added to the history, or put that instead? Because I think history has more than enough text already. That sounds good though what you've written.

--[[User:Z3289066|Elisabeth Karsten]] 11:27, 1 October 2011 (EST)

Cheers Liz! Also I went through the history and took aboard some of the critical comments that people wrote on our project wall. Leaving the timeline in place, how do you think the history section would look if we added the following:

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; gynecomastia, azoospermia, hyalinised and small testes, absent spermatogenesis, elevated levels of follicle-stimulating hormone (FSH) and hypogonadism. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>.
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient<ref name="PMID17415352"/>. This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref><pubmed> 13632697</pubmed></ref>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome<ref name="PMID3529433"/>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

--[[User:Z3289991|Robert Klein]] 11:17, 1 October 2011 (EST)

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No worries, looks good thanks rob. Yeh I went through and deleted a big chunk, but it still looks pretty long hey? I'll give that a go, thanks.
--[[User:Z3289066|Elisabeth Karsten]] 09:51, 1 October 2011 (EST)

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After reading the critique comments, I am proposing that we modify the introduction to something like:

First discovered in 1942, Klinefelter's syndrome is caused by the addition of one or more X chromosome(s) in affected males<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>. He depicted a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis. There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

People were suggesting that our original introduction is too long. What do you all think of this?--[[User:Z3289991|Robert Klein]] 07:19, 1 October 2011 (EST)

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Everyone,
Firstly forgive my absence from the last lab. It was Jewish New Year so happy new year to all!! Secondly, I will have another look at epidemiology, introduction and glossary and see if I can fix it up according to all the comments listed. I can get this properly done later today.
--[[User:Z3289991|Robert Klein]] 06:14, 1 October 2011 (EST)

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Hey guys, so we're now able to fix up the page for final submission. If you haven't already gone through the peer assessment, it would be good to do that. From what has been said I've changed the intro around a bit, let me know if I should change it more. I've also fixed up the references so there are no duplications. If you see any, just make sure to fix it up. If you're not sure how to do it I can show you in lab next week, or else just let me know and I can give it a go.

I was also talking to Dona during the lab, and we were thinking that (as was mentioned in the peer assessment) we probably only need one section on Non-disjunction, I know they say different things, but it might be better to combine the sections. I feel they would fit better in aetiology, then maybe the genetics section would fit better in pathogenesis? That was just my opinion really, if you've got any other idea just let us know.

We were also thinking (from looking at the other pages) we should get more interactive things, so diagrams, images, we've probably got enough tables. But a quote or two would look nice, I thought they were a good addition on the other pages. Maybe that would fit nicely into history?

Sorry about the long message, hope it helps and we can get this fixed up. Though I think we've already got a lot of good information. I plan to add a bit to the research section regarding "Future Research", and I'll be looking for more images today.
Good luck!!

--[[User:Z3289066|Elisabeth Karsten]] 12:22, 30 September 2011 (EST)

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==Peer Review==

A great Effort can been throughout the page. Some of these comments may be helpful.
*Introduction is well researched and referenced but I reckon it’s too long for introducing the topic.
* The History needs to be more organised in a way : like each year should have a separate paragraph. It will make it easier to read.
*Aetiology is well structured, however, I noticed the image needs a reference and a source.
*The Alignment of both images in the Pathogenesis section need to be adjusted to either sides.
* images are missing from the Signs and symptoms. In the table, Puberty and adulthood seem to miss the reference of the source.
* Great work on the table “Other Similar Defects” and the glossary.
* in General, Solid work on the page, references are enough evidence. One Last comment, avoid the repetition of the references(1,3) and some others need to be re-formatted ( 35,36) z3284061

'''Group 3'''

* The introduction is a little text heavy and might need to summarised
* The timeline could be longer
* Image in the Aetiology section is lacking a copyright notice
* The links in Aetiology are good
* An image would be good in Sign and Symptoms
* Pathogenesis needs more referencing
* Some information has been repeated in more than one section
* Links to the Glossary might be useful
* Overall its a good job
--[[User:Z3292953|z3292953]] 11:10, 29 September 2011 (EST)

'''''Klinefelter's Syndrome (Group 3) Peer Review:'''''

Introduction: Information needs to gloss over the entire page a little bit more. Also, the image used has not been referenced correctly and needs to have a copyright notice and the student template.

History: Seems a bit repetitive at first glance. Would it be possible to combine all of this information into the one table? Otherwise, information is good.

Epidemiology: Information is good, however the picture on the left hand side is too small. They have been referenced well.

Aetiology: Picture in this section is slightly ambiguous. Some readers may get confused. Possible more information as to what the picture is portraying. Also, reference the picture and make sure it has a copyright notice.

Pathogenesis: Good information and great hand-drawn images. Possibly need to be slightly larger and explained further. Only 2 references in this whole section?

Signs and Symptoms: Good, succinct list. However, maybe a bit more description? Also, images seem out of place. The images need to have correct referencing format and need to contain the student template. First image is too small.

Diagnosis: Good information. Image needs proper referencing and student template.

Management: Image needs a label at the bottom. Otherwise good image.

Other Similar Defects: This section was well done!

Current Research: Good information but possibly break up the text with a picture or two.
Well done and good luck with editing! --[[User:Z3290808|z3290808]] 10:41, 29 September 2011 (EST)

Klinefelter’s Syndrome – Group 3

* I thought the introduction was very thorough however it didn’t really flow and came across as rather disjunct. Maybe you could actually be a little briefer in this section as it does contain a lot of detail that could possibly serve better in other sections. Good use of image in this section.
* Good use of the table in the history section, maybe an image in this section would look nice also. Use of bullet points as suggested by other reviewers might help to give a more succinct overview, but I thought the writing in this section served well.
* Putting both images in the Epidemiology section on the right side of the page I think would look better, also the sizing looks like they could be matched.
* Aetiology is very well written. Good use of images.
* Some of the pictures need to be referenced correctly and also a little more detail once you click on the images is needed to help explain exactly what is being shown.
* Missing pics in Signs and Symptoms table. Maybe if its hard to find some you could remove this heading from the table and just have the images offset, as then it would not look incomplete.
* Some formatting issues in diagnosis section. I liked the inclusion of the movie clip.
* Current research could be better elaborated. Good explanation of papers however it doesn’t give an overall feel of what is happening in the field. Also the inclusion of future research direction could be an important point.
* Glossary a little incomplete.

--[[User:Z3288196|Z3288196]] 10:39, 29 September 2011 (EST)

'''Peer Review'''
You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

Oh and... YOU DON'T NEED X-CHROMOSOME IN GLOSSARY. The 16yo girl sitting in this lab knows what this means...
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:28, 29 September 2011 (EST)

Group 3:

The long introduction and history needs a pic.

The pictures in epidemiology are really small.

Links to the videos are a good idea.

There is an inconsistent amount of referencing throughout the various sections. Some sections have an excessive amount of referencing and others have just enough. Maybe 2-4 a section.

The references take up quite a bit of the page most probably because there are repeated references that have not yet been addressed.

z3332178 =]

'''Group 3:'''

*intro: the structure of this is a little confusing and it’s not really clear what you’re talking about. The flow of this section is really important – think ‘if I read it on a wiki page, would I read any further, or would I search a different page cos this was just too confusing?’ It might be good to start off your first sentence introducing the disease instead of talking about what happens in normal meiosis first. These few sentences that you put in the middle would be a good few opening sentences.. ‘One of these is known as Klinefelter's syndrome. This describes a syndrome where a person may have one or more extra X chromosomes. This is most commonly due to a process known as non-disjunction during meiosis,’ but start off with ‘Klinefelter’s syndrome is….’ But the content was good.

*history: this section was good with content and structure, but perhaps replace the second paragraph that has all the wordy dates with the timeline and stick your references there. Sometimes it works better with fewer words in a table than a chunky paragraph.

*epidemiology: making the pictures bigger would be nicer. Also theres a lot of info about stuff I would read under clinical manifestations which should be placed there instead.

*etiology: overall good section. The images were really useful. Loved the animation hyperlinks.

*patho: working on the ‘nondisjunction’ to be in one continuous line under the images would be easier to read on the viewer. Other than that, good section.

*signs and symptoms: good section. Easy to read. Concise.

*diagnostics, and the following subheadings: were all easy, well written, flow was good.

*glossary: really liked how you subheaded each part of the alphabet with the letters ‘A’, ‘B’ etc.

--[[User:Z3290558|z3290558]] 09:56, 29 September 2011 (EST)

'''Peer Review'''

:*The first paragraph is not necessary, talk about Klinefelter’s specifically not about sex chromosomes. This can be discussed further in the webpage.
:*Double spacing of paragraphs and other formatting looks awkward.
:*Great historic information but could be integrated into the timeline instead of having large paragraphs and a timeline.
:*Really liked “other similar disorders”. Great idea.
:*Some references need to be fixed so there is not double ups in the reference list.

--[[User:Z3217043|z3217043]] 08:55, 29 September 2011 (EST)

'''Peer Review'''

The wiki has overall interesting information and is well structured. You have also taken all of Mark Hill's suggestions and improved on the site a lot. Some issues:

:*Introduction is a little confusing and not very understood well. Should start off with Klinefelter’s description.

:*Some images are too small. To expand images while reading the wiki breaks up the flow, especially the table images.

:*I don't like the break-up of the alphabet letters in every title on the Glossary section; I find it very distracting.

--[[User:Z3293267|z3293267]] 08:53, 29 September 2011 (EST)

'''Peer Review'''

*Intro: Not a very good idea to introduce the disease with an overly simplified/unexciting image of meiosis, especially if you want the responder to keep reading. I’m sure there something more exciting to represent the disease.

*History: Thorough research, you just have to find a better way of representing it. Take the text, break it down and add it to the timeline. If I was given this to read I would look at the timeline and skip the text, it’s too much.

*Epidemiology: image: “Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png”. The png should not be left at the end of image and quite honestly the table is hard to understand with little explanation given. Wouldn’t people ask what is “ F(1,27= 5.9, p=0.02”? Either explain the table thoroughly or get rid of it.

*Aetiology: Animations were excellent! Perhaps use still-frames as images in this section, because the picture provided is a bit dull and looks very similar to the opening image.

*Pathogenesis: The two images look very similar; perhaps use different colours to indicate their differences. It will make the page more appealing also. The information is relative and easy to follow, although some information is overlapping with aetiology.

*Signs and symptoms: Love the table format- but more information is required. More detail on each section and corresponding images would improve it. Also there is no referencing in the “puberty” section.

*Management:“Action of Amoratase Inhibitors on Production of Estradiol.JPG” is not referenced.

*Other similar defects: It’s a lot more thorough than a few of the sections explaining the disease itself. I don’t think you need to be this descriptive in this section.

*Image/text ratio: need more interesting images (no more cell division images though), and also need to be more detailed in a few sections as mentioned above.

*Overall: Good job, but you still have some work to do.

--[[User:Z3290270|z3290270]] 02:35, 29 September 2011 (EST)

'''Group 3 Peer evaluation'''

*The introduction is good. It brief and informative of what t o expect in the page. The only criticism I have is that the historical background that was placed towards the end of the section, which should probably have been in the beginning or incorporated somewhere there.
*The History section is good, but probably too detailed. I think you can mix the timeline and history together and make this section a bit more concise.
*Epidemiology is a bit of a disappointment for me. There is a bit of information of the demographics of the disease, like prevalence, but I think epidemiology should go deeper into it, like talking about geographical distribution or if there is any race that are more inclined to developing the syndrome. Also this section ended up being an in-depth illustration of a patient’s clinical manifestation. Probably a few statistics on what percentage shows these different types of manifestation and figures some figures of the variation in mutation.
*The etiology section is very informative and I think it has all the information needed for that section. I just think that the arrangement of the information could probably be changed a bit. I think the genetics subsection is unnecessary, even though it does break the section up a bit and allows categorization of it. I just think that you could organise the ideas in this section better than what it already is. The image used here was very appropriate and aids the reader.
*I really like your pathogenesis section. It’s simple yet informative. It is very effective because the terms and concepts that you guys have here are not foreign to the reader because you have already introduced them beforehand, or explained it. Only downfall I guess is the referencing. There is only one section of your information that is referenced.
*Signs and symptoms are done well. You got away with just listing them because most of it is self-explanatory. I guess the only thing that will make this section amazing are some more elaborate images.
*Diagnosis section is done quite well, although the heading should be reconsidered to something like diagnostic test/procedure or something because the diagnosis is “klinefelter’s syndrome”. You also did a good job in incorporating what the tests are looking for, especially in the karyotyping bit. Unfortunately, this was not done for prenatal diagnosis methods, so a bit more information on this one. Finally, I don’t think the statistics need a whole subheading for it. It could just be part of an introduction to this section.
*I like the management section and the image that you used with it is used appropriately and very useful
*The other similar defects is informative, but I think that you went into far too much detail for it in a page dedicated for klinefelter’s syndrome. It is written well and the information in it are amazing though.
*I like the current research section because it says to the reader that the information on this page are up-to-date, giving the whole page credibility. What would probably make it better is a future direction kind of area, where you can put in some proposed theories or studies by researchers, and at the same time some of your own ideas of the direction where this syndrome should head into.
*I am not a big fan of glossaries, but it does look good
--[[User:Z3290841|z3290841]] 10:21, 29 September 2011 (EST)

'''Peer Review Assessment'''
*Overall, good use of sub headings and layout.
*Maybe start the introduction with the actual disease rather explaining the genetics behind it. Got a bit boring. However rest of it was well written.
*History section is well researched. Table is a good summary of the key events. Try and insert an image in this section to break up the heavy text and bring some color into the page.
*The epidemiology section contains information about clinical manifestations and appearances that can be included in a different section. Try and refine this section a little bit. Enlarge the two images in this section.
*Aetiology was well written. It might be a good idea to include some text below the student drawing included in this section explaining it. It doesn't make much sense at the moment.
*I liked the pathogenesis and sign and symptoms sections
*Liked his 'other similar defects' table. Explains the information quite well.
*Very well researched assignment.
--[[User:Z3291622|Z3291622]] 01:23, 29 September 2011 (EST)

'''Peer Review'''
* Picture under "management" is not explained.
* Introduction properly touches on all the topics elucidated later without crossing over too much.
* History is made relevant, linking it to Signs and Symptoms as well as Aetiology.
* Pathogenesis needs more references, as could Signs and Symptoms.
* The layout of Diagnosis At Birth is peculiar.
* Signs and Symptoms could use more demonstrative pictures.
* Glossary is fairly comprehensive.
* Use of related diseases section is interesting, but perhaps should be included within Diagnosis under "Differential diagnoses" or something similar....
--[[User:Z3290689|z3290689]] 00:28, 29 September 2011 (EST)

'''Peer Review for Group 3'''

*The first paragraph of the introduction could be inversed so it can actually start with what Klienfelters syndrome.
*Introduction seems a bit long, making it a bit briefer will capture the audience’s attention better.
*Within the history section the dates should be in bold so that it is easier to follow the information in this section. However, the history does give a good background to the syndrome.
*Table with major advancements is well done
*Epidemiology includes alot of information that doesn’t relate to epidemiological studies, and rather talk about clinical manifestations of people with the syndrome. Maybe put this type of information under another title.
*Figure 4 in the aetiology section should be explained more so that readers could understand what they are looking at.
*The genetics section under the aetiology is interesting, but is it necessary for it to be there, or how does that info link to Klienfelters Syndrome?
*Genetic pathogenesis is explained well. I think the two diagrams should go after the non-disjunction paragraph as it will make the page look better. Also you could talk about how this problem produces the problems for the patients throughout their life.
*Good use of table and dot points in the signs ans symptoms page. It will look good if you have a picture for all categories as you already have 2.
*In the diagnosis section, a little effort should be made to explain how karyotyping occurs as it will make that part better. Other than that the section is good
*I like the ‘other similar defects’ section as it allows the reader to compare and contrast klienfelters with other diseases
*Current research presents a picture to the reader about the current research area for klienfelters.
*Referencing MUST be fixed up as there is repetitive referencing seen in the list.

--[[User:Z3291317|Z3291317]] 23:43, 28 September 2011 (EST)

'''Group 3'''

Introduction: I think you need to explain what the disease is before you explain the genetics behind it. Also, this section seems more like a summary of the whole project. I think you could change it a bit to include more general information on the background of the disease before going into detail.

History: I think this section would be good if all the text was incorporated into the timetable and some pictures added to balance out the text.

Epidemiology: Good section overall however, the pictures could be a lot bigger.

Etiology: Good section but I think the picture needs a caption to explain what the diagram is referring to.

Pathogenesis: This section is clearly explained. The pictures are great but need to be bigger.

Signs and symptoms: The table is good but I think it would look much better if you added pictures for all the sections.

Diagnosis: Similar advice to most other sections- the text is good but I think you should add some pictures to demonstrate some of the abnormalities.

Management: The picture would be good with a caption to explain what the diagram means.

Defects: The table is good but a couple of the pictures are far too small.

Current research: Good section, but again, needs some pictures!
--[[User:Z3291324|z3291324]] 23:20, 28 September 2011 (EST)

Group 3

Hi, overall, a nice project page with interesting information.

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: Nice introduction, good flow and easy to read. However, image needs proper information and perhaps 'This disorder was first described by Harry F.' could be placed earlier on in the intro rather than in the middle
#* History: Nice section, very interesting
#* Epidemiology: First paragraph is good, but I feel the rest of this section doesn't quite belong here, such as the information on seizures, IQs, diagnosis. This section should focus on stats (sex/birth/ethnic/demographic/etc). Fig 2, 3 belong more in the signs and symptoms
#* Etiology: the '1:1000 male' contradicts the '1:500' given in epidemiology. Fig4 needs coyright information
#* Pathogenesis: Needs better referencing, also placing fig 5, 6 on either side doesn't look too good with the text. Perhaps place them below one another?
#* Signs: Seems a bit incomplete, it'll also be good to explain the image of 'pubertal gynecomastia'
#* Diagnosis: Sentence structure could be improved, ie. 'performed because physicians may suspect it because of clinical findings'. Information is interesting, but could be presented more clearly, perhaps in a table?
#* Similar defects: very nice, presented well with good information, easy to read
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Good images used with a nice range of self drawn images. However, lot of the images need to be formatted properly with required information
#Content is correctly cited and referenced.
#* overall referencing was well done, except pathogenesis needs more referencing
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* Nice range of references used
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
#* The information is there, but maybe from now til final assessment, you could do further research in all sections, as they do seem a little short.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* better page layout
* glossary: sorry, but I feel the alphabet subheadings here are not very effective as you have it in alphabetical order anyway

--[[User:Z3291643|z3291643]] 22:01, 28 September 2011 (EST)

'''Group 3:'''

•Good subheading structure, the page flows nicely

•Some parts of the introduction need to be reworded and it should start with an explanation of Klinefelter’s rather than the description of meiosis which is i think is unnecessary at the very beginning of the page.

•Detailed history in the text section, however is the timeline finished? Research after 1970 needs to be completed.

•Glossary needs to be completed, and i’m not sure if you need the separate headings for each letter in the glossary as it spreads it all out a lot.

•Lots of the references are repeated

--[[User:Z3332183|z3332183]] 21:25, 28 September 2011 (EST)

'''Peer Assessment Group 3 Klinefelter's Syndrome'''
*Your introduction is interesting and a good summary of the page
*The history is good however could use a picture
*The images under 'Epidemiology' have quite poor resolution, can hardly read them
*The rest of the page looks great and I have no more to add.
*It is easy to read, well balanced text and pictures and informative
--[[User:Z3308968|Tahmina Lata]] 20:54, 28 September 2011 (EST)

'''Group 3: Peer Assessment'''
* You have constructed an informative page about an interesting syndrome
* At this stage it's a little text heavy, so may be you can cut it down and add some pictures instead
* In the history section it would be great to see these dates from the table with the text blended in, so it's on chronologic flow.
* You seem to take it very serious with the mitosis or not communicating with each other because you have four pictures of mitosis in three different sections. One picture and a good explanation would be sufficient. Then you could use the rest of the space for other pictures.
* The table for signs ad symptoms is great, but looks a bid empty. So may be you can change the format or add some more pictures.
* May be you could write a bid more about therapeutic options. I would find that more important then "similar abnormalities"
* Good referencing through the section. Just change the "double referencing"
* Overall, you page has a lot of information, may be you can balance it a little more out, communicate so you don't have "double" information and a few more pictures would be great.
--z3279511 17:08, 28 September 2011 (EST)

'''GROUP 3 Peer Assessment: Klinefelter's Syndrome'''
*I feel that the introduction is too lengthy, it should be summarised a little more. Although the info is informative, its structure needs some work- grammar and punctuation should be reviewed and sentence structure could be improved
*Figure 1 could use a more descriptive legend
*Historical information is ok, maybe could be improved by extending the timeline to a more resent years, also an image wouldn't hurt, just to break up the text a little
*epidemiology could use some proof reading to correct minor grammar mistakes e.g. "Males born with Klinefelter syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes", sentence structure could also be reviewed so this section flows better (some sentences are short, but other than this, this section is informative
*Incidence is repeated twice, maybe could stick to one section, and it's different in each section (1 in 50 000 or 1 of every 1000 male births?)
*Aetiology (don't really know what this means), and the subheading "genetics" could be a better choice for the whole section, but info here is informative and understandable
*I do like the links made in Aetiology, the picture in this section could use a better legend and needs to be referenced properly (no copyright statement?)
*There is overlapping info in the Aetiology and Pathogenesis sections (both have Non-disjunction as subheading), and both have the same sort of images
*Table in signs and symptoms is too small should be a lot bigger so detail can be seen, it also needs to be referenced properly
*The info for signs and symptoms is good in a table, but it would be better if the table had colour so the reader can distinguish each section of the table
*diagnosis is informative

Overall:
*Reference list needs some work, some of the references have been repeated
*Project could be improved by finalising the glossary and maybe linking the words in the body to the glossary itself
*Images need to be referenced properly and some need more informative legends
*I feel some of the information is a little repetitive, maybe could read through and edit so it flows better
*subheadings and headings could be reviewed and re-organised so page flows better
*I do like the feature of links added throughout, maybe more would make it better

--[[User:Z3331556|z3331556]] 14:28, 28 September 2011 (EST)

'''Group 3 Peer Assessment'''
* Try to link your sentences in general - at times the reading is quite disjunct and difficult to read. Try to rewrite sections and see if it can be written in a more succinct manner.
* In general, keep the images on the right hand side of the page - I know you want to break things up, but if images are kept on the left then it disrupts the paragraph lining and makes the information difficult to track with the eye (just a minor thing, this is my opinion anyway)
* Some subsections just appear too short; is it really necessary to make a subsection for one or two sentences, as is the case of karyotyping? Try to implement all of the information into one paragraph
* The first image requires a proper reference to the work; is there any copyright information? And also protect your hand-drawn images - they are drawn excellently, but have no copyright information (unless you are happy with the images been used straight away by other students! :) )
* The current research section and possible treatment options section is far too brief; if this is a syndrome that causes many problems, then there should be a fair amount describing our direction of research and methods in which we can combat this syndrome. Try to find more information here!
* Overall, a good balance of the images and format, but reconsider the structure of paragraphs and subheadings so that the entire project has a better feel. Many sections feel like they have been started with great enthusiasm, but this has burnt out over time, giving the project a feel that some sections are just left incomplete. Try to fix this!
--[[User:Z3288827|Leonard Tiong]] 09:37, 28 September 2011 (EST)

'''Peer Assessment'''
*The first two paras of the introduction belongs in the genetics/etiology section. Need a broad intro to the actual syndrome and what happens in it. You don’t need to give a brief overview of all the sections, this isn’t an English essay.
*History- break up with bullet points?
*Figure 3 is a bit small – a bigger pic will look better I think
*Pictures in the Pathogenesis section look funny with the text – maybe have one under the other? It just squares the text in the middle and it looks odd.
*Don’t forget the missing pics in the signs and symptoms table
*History/timeline table might look better in purple – keep it consistent with the others.
*In the Current Research section, the 2nd paper that you have described is written with very colloquial language – can’t use that here! Maybe have a brief intro para about current research and where its headed etc, not just a description of papers. Also, maybe link them to other papers, e.g. This paper shows similar results to _______, surely there are similar findings in particular areas of research?
*Fertility picture needs to be in a ‘Figure’ box with a description and explanation of what it means.
--[[User:Z3332824|z3332824]] 23:30, 27 September 2011 (EST)

'''Group 3'''

*I think the introduction should be a little more concise
*History could work better if all the information was summarised in a table/timeline rather than having paragraphs then a timeline. *Also, I find it a little hard to believe that no findings have been made since the 1970s.
*Epidemiology would probably benefit with subheadings
*Signs and symptoms are nicely set out
*I like that you have added a comparison of other diseases
*Maybe add a few more researches from 2011 rather than 2010 (if possible)
*Overall, quite a good project with some minor adjustments needed

Group 3:

*Whilst I appreciate the introduction and its content, I feel an introduction doesn’t need to be of the same size as some of the other sections of the project. It is to give a mere idea of the condition.
*History could be broken apart with dot points or bolded dates instead. How about a picture of Harry Klinefelter?
*Aetiology picture has no link to the article or where it was found, and no copyright notice.
*Pathogenesis has very little references, surely more would have been used.
*Images in table are blank and a lot more references would have been used than shown.
*space out the subheadings so they don’t look disjointed in diagnosis.
* references have not been listed properly (various links for same article)
--[[User:Z3291423|z3291423]] 18:09, 27 September 2011 (EST)

Group 3: Klinefelter’s Syndrome
*overall look: inconsistent formatting, imbalance of text and images in some sections, appropriate headings used.
*introduction: very broad, maybe too much detail?
*history is well researched; I really like the timeline at the end which summarises the major advancements. But it is very short and ends in the 1970s. It could include current research/advancements.
*Epidemiology: could benefit from a few subheadings or breaks in the text.
*Aetiology: I really like the use of external links.
*Signs and symptoms: works well in a table format but not sure why some cells are coloured and others are not.
*Other similar defects: interesting addition to the webpage, allows audience to continue research. Also demonstrates extensive knowledge of the syndrome. Great idea!
*Minor adjustment: just for convenience, glossary terms could be linked
--[[User:Z3332327|z3332327]] 16:14, 27 September 2011 (EST)

'''Group 3 assessment:'''
*Introduction begins in a confusing manner should begin explaining the disorder Klinefelter’s syndrome before explaining the genetic component of meiosis. Where the image was explained though would be more beneficial if the introduction have an image of the founder of the syndrome within this section or within the history heading.
*History has clear structure with explained information of the progress with relation to the timeline of the syndrome, images would have been more useful within this sub heading to make livelier instead or too much text.
*Epidemiology detains the male component though could explain female areas related to syndrome as well figure 3 .
*Pathogenesis is organised with images placed in areas which bring upon confusion where fig 5 and 6 both linking to Non-disjunction, image placement beneath text would be better placement.
*Signs and symptoms could have a little more elaboration and/or more images
*Sub heading of diagnosis at birth needs to place either in the centre or down 1 sentenced to become more organised.
*References should remove any repeats and the links below should be manually added to the references either under another subheading or normally
*Glossary should be linked throughout, either linking the word to the glossary or even bolding the terms so no confusion for people without any background in the area can understand.
z3332250 23:43, 26 September 2011 (EST)

Group 3 Peer Review

*Well structured and organised
*Timeline seems odd that it ends at 1970? If further information cannot be found, try to present this in a different way
*Figure 2 and 3 could perhaps be a little bigger
*Should a copyright statement be included in some of the images?
*Signs and symptoms table is great
*Some duplication of information throughout page-unnecessary
*Video link is a nice extra
*Well balanced text, images, and tables/graphs
*Overall, a well written page and visually appealing
--[[User:Z3308965|Fleur McGregor]] 18:48, 26 September 2011 (EST)

===Comments on Group Project 3===

Group 3

*Introduction seems a bit wayward to begin with. Maybe introduce the syndrome first and then briefly explain meiosis, it just seems a bit indirect. I like how the intro touches on some aspects to be described later in the page but, good work.
*History section could be organised a bit better I think, the combination of text and timeline is good but there must be a balance, right now there’s a big block of text and a teeny timeline
*People might have already said this but I think the epidemiology section is too broad and covers topics outside of its section (clinically diagnosed characteristics and such)
*Aetiology – I definitely like this section, the image is perfect and relates to the non-disjunction paragraph, information provided here is clear and easy to understand.
*Pathogenesis – maybe consider reformatting the images so that the information under ‘Anaphase Lagging’ is easier to read, and the heading ‘Nondisjunctiom’ is not in the middle, would add to continuity and the flow of the entire page if all headings were aligned to one side
*Other Similar Defects – this table is really hard to read, but the information is good, although it does need to be referenced properly
*Nice glossary and current research headings, I don’t really see anything to fix. Good job guys.

--[[User:Z3331469|z3331469]] 06:58, 29 September 2011 (EST)

'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

--Z3389806 07:08, 26 September 2011 (EST)

'''Group 3'''

*Introducton: the beginning is a bit to abrupt, very nice image, otherwise good content

*History: very detailed information, useful timeline

*Epdidemiology: fig.3 would look better on the right side, the content is good

*Aetiology: no copyright information for the image, good use of subheadings.

*Pathodenesis: again, figure would look better on the right side, it disrupts the flow.

*Signs and symptoms: good table, the images look a little lost though, so maybe place them on the right edge, “age and intellect” could be bigger.

*Diagnosis: well done

*Management: good content, nice flow

*Similar defects: good content, but the structure could be better, maybe place the content in a table without the dots. Everything that belongs to e.g XO should start at the same hight

*Research: interesting section, well done

*Glossary: seems incomplete

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 12:13, 25 September 2011 (EST)

Group 3
* The first thing I noticed is that the project is very text heavy. Also- there are 4 images of mitosis. Is this really necessary? One is enough and you can use the other spaces to put other images in
* The introduction gives a nice, broad overview of the project. I understand immediately what is going to be said. But is there not an image of a patient to put here to draw the reader in? Maybe its just me that isn’t very excited about images of mitosis sorry.
* The history section would work better as a list of dates and names rather than a bulk of text
* Has there been no research since the 1970s? More recent findings need to be added to the history
* The epidemiology is very interesting- but there is a lot of clinical manifestations here that are described later. There is a double up in information.
* Signs and symptoms works well in a table- but more images of the condition would make it even better
* The comparison of other conditions is excellent! Great idea.
* Your information is there is just needs to be organised a little better and the fact that you have double ups on information and pictures indicates that there may not be any communication in the team- either that or laziness to find a different picture. Look forward to seeing your final project!

'''Group 3'''
* Good over all structure with the use of headings and sub headings. A very interesting syndrome and the page is easy to read.
* I think the intro could be condensed a little, as it should get straight to the point.
* I enjoyed reading the history section and good use of table and summary of history.
* I like figure 1, very nice that it was done by a student!
* figure 4 Maternal Non-Disjunction.. Is this a student drawn pic or did you use it from somewhere.. a little unclear.
* I was nice to see sign and symptoms tabulated, which made this section very easy to read and understand. good use of picture here. Could you find anymore relating to the signs and symptoms?
* I liked the addition of a movie link.
* The sub heading of diagnosis were very appropriate.
* Other Similar Defects- very interesting to add this in..
* Interesting current research: nice that it has been summarised.
* Make sure your reference list hasn't doubled up.
* Just for clarity it might be nice to use the same colour table throughout the page.
* It was good to see some of your pictures correctly labelled.

*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?
The genetics part is good though.
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.
*'''Management''': Looks good.
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.

'''Peer Assessment: Group Project 3'''
*The introduction is informative, however I think that the small paragraphs at the end detract from the section as a whole. It would be better to integrate these more so that they flow on from the previous text.
*The history section provides both detailed information and a timeline, which makes the historical stages easy to comprehend and refer back to.
*Is the image in the section on aetiology drawn by a student? If not, then copyright information and referencing needs to be included.
*In the section on diagnostic procedures, the image could be placed on the right for ease of reading.
*The figure in the signs and symptoms section and the figures in the epidemiology section are too small.
*Using colour borders in the signs and symptoms table would make it a bit clearer.
*The links to animations and a movie are great uses of additional material.
*Under the information in some of the images you have uploaded, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*The references should not be duplicated and can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
--[[User:Z3217345|z3217345]] 13:28, 27 September 2011 (EST)

'''Group 3 Assessment'''
*The Meiotic Non-disjunction jpg doesn’t have the proper citing or information about future referencing abilities.
*In the history section, I like how the occurances are both described in detail and set forth in an easy to read table format. Very organized.
*In the Aetiology section, where is the referencing for the Non-disjunction videos? Is video copyrighted?
*The Aetiology section and Pathogenesis sections seem to contain almost identical information. Are both necessary, or could they be combined/ one deleted?
*If you decide to keep the Non-disjunction videos, are the pictures in the Pathogenesis section necessary? Or do they just become redundant?
*In the Epidemiology section, both pictures need to be enlarged; they are so small I can’t make a distinction as to what’s on them.
*Signs and Symptoms- This section overall looks very good as far as information goes. The only thing I would suggest is to separate the different age sections a little bit more; their symptoms look to be running together from group to group. Also, try increasing the picture sizes, as they (especially the first one) is difficult to read.
*Again, for the video under Karyotyping, where is the referencing and copyright information on this?
*Action of Amoratase picture- This still needs to have the disclosure statement reguarding re-use and copyright guidelines. Also needs a descriptor sentence below the picture.
*Glossary- Shouldn’t there be references for these definitions?
*Both the Similar Defects and Research sections seem decent. Only suggestions:

-Similar defects chart: Try bigger pictures and sentences of less length.

-Research- Try adding a picture to the section to make it more aesthetically appealing
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
--[[User:Z3391078|Ashley Smith]] 14:00, 27 September 2011 (EST)

'''Group 3:'''
* The introduction is very lengthy, some parts feel as though they would be more appropriate in other sections. The image here fits nicely with the text but it could benefit from a more descriptive legend and needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>.
* In the history, you begin to use the short hand “KS” without an initially stating that this is the abbreviation for “Klinefelters syndrome (KS)”. The dates that are mentioned are very detailed although it ends in 1970, were there any other breakthroughs since then? A picture of Klinefelter would be a nice touch here.
* Epidemiology requires some proof reading as there are a couple of little mistakes and the images would have more of an impact if they were slightly larger.
* I like how you have linked figure 1 to the non-disjunction sub-heading under aetiology. The image in this section could benefit from a coloured legend, ie. Instead of saying “Blue circles are male cells”, in a box include an actual blue circle = male cells along with the other descriptions. It also needs to be properly cited.
* There is too much repetition between pathogenesis and aetiology, maybe discussion between these two students is needed to minimise repetition. Good hand drawn images but you need to include the student template as mentioned previously.
* Signs and symptoms would look better in a coloured table and with more images. I don’t think it is necessary to repeat the image comparing age and intellect here.
* Diagnosis; nice use of another form of media – a video. The abbreviation of KS in this section needs to be established first by placing KS after the first time you mention Klinefelters syndrome.
* Management is very concise and thorough
* Other similar defects; nice touch, it could look more appealing with the use of colour and larger images though.
* Current research is formatted nicely and flows well

'''Group 3 - Peer assessment'''

*The introduction is abit lengthy and choppy because some paragraphs are just 1-2 sentences. Maybe try to connect them into one paragraph and try to make it flow better.
*The history was quite informative maybe put the timeline at the top and the text at the bottom and maybe try to add more recent dates.
*Epidemiology - the use of figures are good and it is explained well in the text
*Aetiology - good idea in external linking images! the information is easy to easy as it is well structured
*Signs and Symptoms - the table is abit confusing to read, althought the information is well reduced
*Other Similar Defects - maybe the use of lines within the table would be better to separate the columns and rows because it is abit hard to read

--[[User:Z3330313|z3330313]] 19:50, 28 September 2011 (EST)

--z3290815 15:54, 28 September 2011 (EST)

'''Peer Review'''

* a lot of writing and so makes the wikipage interesting to read
* the image in the pathogenesis section needs fixing
* the image layout is not organised well
* needed to explain Klinefelter's disorder in simple terms. I could understand it but if it was explained in a more simple way it would be much better.

--[[User:Z3060621|z3060621]] 20:58, 28 September 2011 (EST)

'''Group 3'''
'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are present.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Under aetiology, it might be good to add a sentence or two about the cause of Klinefelter's Syndrome rather than just jump right into aneuploidy. I understand that it is the aetoilogical agent in Klinfelter's but indicating it as a cause would be good to kinda give the reader a 'flag'. It is not necessary to add the information about aneuploidy in the introduction as i think you could move that section down to a more appropriate part. If need be, just mention aneuploidy as a cause in the introduction rather than dedicate the first paragraph to it in the intro.

'''*Content is correctly cited and referenced.'''
Maternal Non-Disjunction.PNG needs some references, Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG, Pubertal gynecomastia.jpg, Immunoglobulin levels in 15 girls with Turner Syndrome.png and Karyogram of male with 47, XYY Syndrome.png needs to be correctly referenced. duplication of references need to be fixed. More references need to be included when there is a huge chunk of text or it looks very much like you got everything from one source only.

'''*The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.'''
Good drawings - explanations are understandable.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
There is a significant reference list but not enough in-text referencing.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
A lot of content on genetic problems, maybe put something in about development of embryo (if applicable)?

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has shown development and editing to be based on the above guidelines although some smaller details could be fixed.

--z3329495 21:11, 28 September 2011 (EST)

==Discussion==

----

Hey i have been looking for a profile pic for some time and none have come up. So prob better if you don't look for it because I am afraid that you will waste time. Nice! birthday cake :) I should do that for my dad's bday which is coming up.
Anyways see you tomorrow
--[[User:Z3289301|Dona Cho]] 23:55, 21 September 2011 (EST)

----

Hey Dona, thats a good idea! i like all the pics that you have added, and pathogenesis looks good! I just baked my dad a birthday cake and planning on doing some work on this now. So i will probably be up for a while. I am also looking for pics of H. Klinefelter. Good work!--[[User:Z3289829|Souti Khalil]] 21:12, 21 September 2011 (EST)
----

I am looking for a profile picture of Mr Klinefelter. I think it will be good to put one in in the introduction section. I am having trouble finding any - but you do come across one pls put one up -I think it will look great!
--[[User:Z3289301|Dona Cho]] 20:19, 21 September 2011 (EST)

----

Guys I thought that it would look good if all the images were order 'figure 1, figure2...'
Just so that it all looks uniform
Hope your ok with it but if you don't like it you can just change it back.

--[[User:Z3289301|Dona Cho]] 17:52, 21 September 2011 (EST) :)

----

That looks interesting, but I'm not really up to adding any of that tonight. Feel free to add whatever you like.
--[[User:Z3289066|Elisabeth Karsten]] 22:57, 14 September 2011 (EST)

Hi guys ;)

I was just reading some stuff - found some interesting info related to management (I think it is liz?)

The part of the review is as follows:

'Decreased energy and libido, which are associated with postpubertal testosterone deficit, improve with hormone therapy and often are accompanied by improved confidence and sense of well-being.Androgen therapy should be started when there is direct laboratory evidence of a testosterone deficit or when hypergonadotrophism, which suggests such a deficit, is present. This may occur by the time the patient begins middle school...

Because gynecomastia predisposes men to breast cancer—the frequency of breast cancer is 20 to 50 times greater than in men who do not have Klinefelter syndrome1,2—monthly breast self-examination should be encouraged. If necessary for cosmetic reasons, gynecomastia may be treated surgically.'

The review also mentioned something about 'cryopreservation' so that the precious sperm can be stored and used for later IVF.

If the above sound interesting, it might be good reading the review article (particularly the management section. Follow the link below for the review.

http://www.aafp.org/afp/2005/1201/p2259.pdf

ps. I dont think I will be sleeping much tonight!!

--[[User:Z3289301|Dona Cho]] 22:32, 14 September 2011 (EST)

----

I don't think we can use those pictures, unfortunately. Safest to stick with papers and hand-drawn I think. The timeline looks really really good. If anything, I would be inclined to put a bit less info in the main bit of history and focus on that time line. I think it's a nice visual respresentation of the information.
--[[User:Z3289066|Elisabeth Karsten]] 21:17, 14 September 2011 (EST)

----

I found this website which has alot of picture's of KS, and there are only a few copyright statements, can we use them? [http://carregwenimages.com/klinefelters-syndrome-pictures]

Haha, I just saw them! thanks for that! I just edited the history and the timeline. Is the information in the timeline just repetitive of what i have written, should i just remove it? --[[User:Z3289829|Souti Khalil]] 20:09, 14 September 2011 (EST)
----

It did end up happy in the end lol. Yeh they look really good. We're allowed to add links to our page, so I think that'd be best. I'll put those on now. Thanks!
--[[User:Z3289066|Elisabeth Karsten]] 18:46, 14 September 2011 (EST)

Thanks for fixing up the table in signs and symptoms, it looks great!

That video was mean, i was eating when i watched it and i felt so sorry for the little boy, i couldnt watch the rest. :(

If you think we need an animation i found these two websites, but i have no idea of how we would put them on to our page.

[[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm]]
[[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm]]
--[[User:Z3289829|Souti Khalil]] 18:09, 14 September 2011 (EST)

----

That video is so funny! I was laughing to the point of tears while watching this! I don't think Dr. Hill would be too happy if we added the video to our webpage though. Great job Liz once again with the editing. Keep up the good work!--[[User:Z3289991|Robert Klein]] 15:22, 14 September 2011 (EST)

----

Hey everyone, I just uploaded our 1 Wikipedia image. It's the karyotype of Klinefelter's syndrome. If anyone founds anything better on Wiki, just make sure you say something and take that one off.
--[[User:Z3289066|Elisabeth Karsten]] 09:52, 14 September 2011 (EST)

So I found this video, it's super cute and lame. But I think it's a nice representation? Not sure how applicable it is though... http://www.youtube.com/watch?v=6q2JxMDaNys
--[[User:Z3289066|Elisabeth Karsten]] 10:08, 14 September 2011 (EST)
----

[[File: Signs and Symptoms by Age Group.PNG|right|300px| Signs and Symptoms by Age Group.PNG|thumb]]

Thanks Liz! I really loved the intro and the picture that you created! Maybe we don’t have to remove it, however I will also be on the lookout for a picture which may better suit the introduction. In the meantime, I was thinking maybe we should order the subsections better, for example; Introduction, History, Epidemiology, Aetiology, Pathogenesis, Signs and symptoms, diagnosis, management, other similar defects and then current research. I just think we should explain the cause and pathogenesis of the disease before the signs and symptoms and diagnosis.

Lastly, I found a table on a website and have created a similar one on signs and symptoms. I'll just upload it here, and we can decide if we want to use it.

That is all. --[[User:Z3289829|Souti Khalil]] 13:13, 12 September 2011 (EST)

That table looks really really good, though it could be easier if we upload it like the other table I put up, as opposed to a picture. I'm happy to do that if you like. And yeh that order looks good too, I'll change it now and if anyone disagrees they can change it back. --[[User:Z3289066|Elisabeth Karsten]] 22:29, 12 September 2011 (EST)
----

Our page is starting to looking really good!! I just fixed up the aetiology, it may need more work to be done though. Liz the picture i made, is really similar to the one you have in the introduction, is it too much?? Sorry about the delay in uploading it. --[[User:Z3289829|Souti Khalil]] 00:50, 12 September 2011 (EST)

That's fine, I kind of expected that. You use it since it fits in with your topic and I'll do another one for the intro. Aetiology looks really good, nice work!

--[[User:Z3289066|Elisabeth Karsten]] 09:07, 12 September 2011 (EST)

----
Hey Liz, Great job with the editing! It looks really good. I will keep on the lookout for gathering more information. --[[User:Z3289991|Robert Klein]] 20:31, 11 September 2011 (EST)

----

Hey everyone, I've just fiddled with the formatting of the page a bit. If you don't like it, of course feel free to change. I also changed the formatting of the table t make it a bit clearer to read, if you preferred the old one though I've saved a copy of it so just let me know. Just looking at the page, some things in epidemiology I think would fit a bit better in signs and symptoms; and eitiology and pathogenesis are a little repetive of each other which I guess we should of expected. But we'll be able to discuss it properly on this coming thursday.

--[[User:Z3289066|Elisabeth Karsten]] 20:24, 11 September 2011 (EST)

To help out a bit, I found some links to articles that are 'Open Access'. This should save time for you guys:
http://www.springerlink.com/content/g68408vq74752421/fulltext.pdf
http://psy.hull.ac.uk/Staff/t.jellema/VantWout_PlosONE.pdf
http://www.autismresearchcentre.com/docs/papers/2011_BCetal_Plos%20biology_unsolvedmystery.pdf
http://www.ojrd.com/content/pdf/1750-1172-5-15.pdf
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020292
http://www.hogrefe.nl/fileadmin/user_upload/Documenten/PDF/Wetenschappelijk_onderzoek/Bruining_et_al_-_Dissecting_clinical_heterogeneity_of_ASD_through_genotypes.pdf
http://www.ijponline.net/content/36/1/36

Hope this helps!--[[User:Z3289991|Robert Klein]] 12:23, 9 September 2011 (EST)

Looks good, thanks rob.

--[[User:Z3289066|Elisabeth Karsten]] 20:24, 11 September 2011 (EST)

----

I had to remove the photo from 'signs and symptoms so that I can confirm it's copyright restrictions. Sorry about that. --[[User:Z3289991|Robert Klein]] 07:44, 9 September 2011 (EST)

----

I edited the Epidemiology and fixed it up as best I could. As well, I found and added a picture to the signs and symptoms section to make it a little clearer. I still seem to be having difficulties with formatting. If anyone comes across charts that I can use for Epidemiology, that would be much appreciated. I still can't find anything that I can use. I will fix up the 'other similar defects' section and have it ready very soon. --[[User:Z3289991|Robert Klein]] 06:39, 9 September 2011 (EST)

----

Hey guys, sorry I've been a bit MIA recently. But yeh I agree totally, I was planning to finish off the intro once everything else is finished, but for the moment I'll make sure I'll finish off my other sections.
And yeh you're ideas re:tables and diagrams sounds great. I'll have a go at drawing a couple on paint as well
--[[User:Z3289066|Elisabeth Karsten]] 21:39, 8 September 2011 (EST)

----
Good idea Souti! As well as that, I will retype my sections and try and fix them according to what Dr.Hill wishes. Maybe for treatments, you could speak about the drugs used to manage the condition. We do need to edit the other sections and add much more content and diagrams. Perhaps a few handrawn diagrams wouldn't go astray?--[[User:Z3289991|Robert Klein]] 18:40, 8 September 2011 (EST)

----
Hey guys, I noticed earlier today that Mark Hill has put comments on our page that we need to change and improve. So i'm going to take out 'case study', and replace it with 'treatments'. What do you guys think? Make sure you have a look at what he has said.
--[[User:Z3289829|Souti Khalil]] 17:44, 8 September 2011 (EST)

----

Rob, 'Other Similar Defects' is looking great! I am committing the next couple of hours to Klinefelter's syndrome. Do you guys think we could elaborate a bit more in the introduction, just to give a larger scope of our disease?

--[[User:Z3289829|Souti Khalil]] 11:48, 8 September 2011 (EST)

----

I added images to 'Other Similar Defects'--[[User:Z3289991|Robert Klein]] 07:55, 7 September 2011 (EST)

----

I have constructed a table for Other similar defects! I think that it should be alright, however there may not be enough info so the conditions may not properly be explained. We are still waiting on a table for signs and symptoms as well as a diagram for pathogenesis--[[User:Z3289991|Robert Klein]] 10:01, 6 September 2011 (EST)

----

What we should do is add a table to 'similar defects', a diagram for pathogenesis, a and a table for signs and symptoms--[[User:Z3289991|Robert Klein]] 12:49, 1 September 2011 (EST)

----

Glossary, Epidemiology and Similar defects have all been added. Let me know if anything else needs to be done!--[[User:Z3289991|Robert Klein]] 06:04, 1 September 2011 (EST)

----

Alright Everyone,
For the different genotypes dotpoint, I will cover that when I complete the section to do with 'similar defects'. I have fixed up the referencing system. --[[User:Z3289991|Robert Klein]] 13:53, 27 August 2011 (EST)

----

Hey guys,
I have included a list of things that Mark Hill emphasised in regards to our group project in the lab today;

- Different genotypes

- Animal models

- Review articles

- Importance of how the disease comes about (pathogenesis).

So, by next Thursday our main page should have plenty of content under each subheading. 
--[[User:Z3289829|Souti Khalil]] 14:14, 25 August 2011 (EST)

----

Hey Guys,
I have added a discussion tab for any enquires and updates on the progress of our assessment, as well as a referencing tab (or whatever they are actually called) at the bottom of the page. So for each section, if anyone finds relevant articles/images etc. they can place it there.
Oh, and please remember to add new content to the top.
--[[User:Z3289829|Souti Khalil]] 00:53, 18 August 2011 (EST)

----

Hey Guys,
Sorry to be a bother. I am having trouble referemcing properly in the Wiki format, as what can be seen in my Epidemiology piece and also my messing up of the reference list. Would one of you mind showing me how to fix this problem? Thanks so much and I will have the piece on 'other similar defects' prepared by Saturday. The glossary will be uploaded on Monday.
--[[User:Z3289991|Robert Klein]] 05:40, 18 August 2011 (EST)

----

'''Referencing'''
PMID is the reference number that you need

without the ':' will act as an link to the article
--[[User:Z3289301|Dona Cho]] 12:51, 25 August 2011 (EST)

==References==

If you find any good papers relating to someone elses topic, you can put them under these subheadings to help out.

Hey guys! this is a publication which seem to be pretty good!!

http://www.nichd.nih.gov/publications/pubs/klinefelter.cfm
--[[User:Z3289301|Dona Cho]] 12:54, 25 August 2011 (EST)

===Description/Introduction===

===History===

Natural history of seminiferous tubule degeneration in Klinefelter syndrome<ref><pubmed>16172111</pubmed></ref>

===Signs and Symptoms===

===Epidemiology===

Abramsky L, Chapple J.47, XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn. 1997;17:363–368.

Bojesen A, Juul S, Gravholt CH.Prenatal and postnatal prevalence of Klinefelter syndrome: anational registry study. J Clin Endocrinol Metab. 2003;88:622–626

[http://www.aafp.org/afp/2005/1201/p2259.pdf Klinefelter Syndrome]

===Diagnosis===

Hey guys, it's Dona. I put my name down for this section. I will try to get mine done by the end of this week. :)

--[[User:Z3289301|Dona Cho]] 17:23, 24 August 2011 (EST)

===Treatment===

===Etiology===

===Pathogenesis===

===Case Study===

===Similar Defects===

===Current Research===
http://www.ncbi.nlm.nih.gov/pubmed/7446531
Check this out!!--[[User:Z3289991|Robert Klein]] 05:03, 1 September 2011 (EST)

<ref><pubmed>21342258</pubmed></ref>

===References===
<references/>

==Pictures==
[[File:Magnetic Resonance of Head MRI from patient with Down Syndrome and Klinefelter's Syndrome.jpg|thumb|Magnetic Resonance of Head MRI from patient with Down Syndrome and Klinefelter's Syndrome]]

--[[User:Z3289829|Souti Khalil]] 23:57, 17 August 2011 (EST)

[[File:Klinefelter's Syndrome.jpg|thumb|center|Klinefelter's Syndrome]]

--[[User:Z3289066|Elisabeth Karsten]] 23:31, 13 August 2011 (EST)

[[File:Overview of human testicular sample from a patient with Klinefelter's syndrome.png|thumb|center|Klinefelter's Syndrome patient testicular sample]]

--[[User:Z3289991|Robert Klein]] 10:17, 16 August 2011 (EST)

[[File:Kleinfelter syndrome.jpg|thumb|center|Facial dysmorphic features in a child with double aneuploidy—Down syndrome and Klinefelter syndrome]]

--[[User:Z3289301|Dona Cho]] 20:35, 17 August 2011 (EST)

==Topic Choice==

Hey guys, so after having a look at that list I quite like the sound of
*Anencephaly or
*Klinefelter's syndrome

There's loads of resources for Klinefelter's syndrome, but I think Anencephaly sounds really interesting. It's a type of neural tube defect, so we may even be able to do that as a topic - neural tube defects (it's on the list as well).
Just let us know what you think, thanks guys!

I've just attached a review for each

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

[http://www.ncbi.nlm.nih.gov/pubmed/21110233 Neural Tube Defects] or [http://www.ncbi.nlm.nih.gov/pubmed/17089587 Anencephaly]

--[[User:Z3289066|z3289066]] 09:32, 6 August 2011 (EST)

Hey Everyone,
I am leaning towards Klinefelter syndrome as it seemed interesting to learn about. I found a couple of articles on the internet which explore more the epidemiology of the condition amongst the population. Liz, I read through your artiles and they were quite interesting in the way that they explored the genetics behind the condition. We will be able to perhaps link these in with the epidemiology to make our argument more convincing.

Below is a review article:

[http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/(SICI)1097-0223(199909)19:9%3C808::AID-PD637%3E3.0.CO;2-B/pdf]

The Research Article:

[http://jcem.endojournals.org/content/88/2/622.full.pdf+html]

Both articles explore more the epidemiology of klinefelter's syndrome as I felt that it would be interesting to look at its prevalence, and frequency of distribution within a population. The first review article that I hasve linked to explores the frequency of Klinefelter's syndrome in a population along with various other genetic anomalies.

--[[User:Z3289991|z3289991]] 07:02, 9 August 2011 (EST)

Yeh that sounds good to me, if anyone has any objections just let us know. We can figure out exactly what we want in the page on thursday, but yeh should def's talk about the epidemiology.

--[[User:Z3289066|z3289066]] 14:53, 9 August 2011 (EST)

Hey guys!

I think that Klinefelter's syndrome is definitely an interesting disease and it has lots of resources. I think we still need a plan B though, a few other diseases which I thought were really interesting are;
- Thalassaemia
- Anencephaly (good pick Liz!)
- Spina Bifida
I found a really good review article on Klinefelter’s syndrome, although it’s pretty dated.
[http://archinte.ama-assn.org.wwwproxy0.library.unsw.edu.au/cgi/content/full/158/12/1309]
[http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/ajmg.b.30163/pdf]

I shall see you all thursday!

--[[User:Z3289829|z3289829]] 22:15, 9 August 2011 (EST)

Hey guys, this is dona - I guess I am the last one to write on the board (sorry!)

I personally like the topic; neural tube defects. Reasons are 1. there is so much information because it is an umbrella term that includes many conditions like spina bifida and anencephaly
and 2. we will be learning the developing of the neural tube next week in lecture - so it will not be difficult to understand the etiology of neural tube defects

Here are the links:

review article [http://www.ncbi.nlm.nih.gov/pubmed/10899792]

research article [http://www.tandfonline.com.wwwproxy0.library.unsw.edu.au/doi/pdf/10.1080/19485565.1991.9988793]

p.s Hey could everyone identify themself by writing their name before writing on this discussion forum, that way people know whose talking. (please)

--[[User:Z3289301|Z3289301]] 17:23, 10 August 2011 (EST)

===Sections===

*Description/Introduction - Liz
*History - Souti
*Signs and Symptoms - Dona
*Epidemiology - Rob
*Treatment - Liz
*Eitology - Souti
*Pathogenesis - Dona
*Similar defects - Rob

I was thinking it'd be good to also do a topic on recent research, I'm happy to do that one, and should also do a glossary. So we should have someone finalise that, but it'd be really helpful if everyone could just add words in they think would be good as you go. Does anyone want to volunteer for editing that? Just put your name in the spot below so everyone knows.

*Recent research - Liz
*Glossary - Rob
*Diagnosis - Dona
*Case Study - Souti

--[[User:Z3289066|Elisabeth Karsten]] 12:15, 13 August 2011 (EST)

----

Hey Guys,
I have uploaded an image to the Epidemiology section of the Group webpage, however it appears to have distorted the whole webpage in that all the other categories below epidemiology have been pushed to the side. Also, I am having trouble trying to enlarge the image. Do you know how I can fix this problem? The table was referenced appropriately.
Cheers

--[[User:Z3289991|z3289991]] 10:14, 13 August 2011 (EST)

Hey, yeh that should be fine for the moment, don't worry too much about the formatting. You can fix it, but it'll be easier to do once there's text there too move around it.
There should be a page explaining all the details about picture formatting, but I can't qutie remember how to do it off the top of my head. Is that the size of the original image? Because that could be part of the problem.

--[[User:Z3289066|Elisabeth Karsten]] 12:09, 13 August 2011 (EST)

Oh I've just realised what's happened, see how you've put the file name then "thumb"? The default for thumb is to make it slightly smaller and move to the right where it will wrap around whatever text is there. You can try [File name|thumb|left|name] if you want it on the left, or else instead of 'left' you can say 'center'. But it's gotta be 'center', not 'centre' (I think). Or else you don't have to use thumb at all, and just leave it out completely.

Hope this helps.

--[[User:Z3289066|Elisabeth Karsten]] 14:02, 13 August 2011 (EST)

Thanks Liz,
You know what? I will add some text during next week and then play around with the formatting. You are right in your first comment, because that way I can format the picture and text properly. Thanks so much for your help though.
--[[User:Z3289991|Robert Klein]] 15:21, 13 August 2011 (EST)

----
==Peer Assessments==

* Great amount of depth, you have covered each subheading quite well
* It was great to see a comparison to other similar defects
* Non-disjunction is discussed twice, can it be summarised into just the one section?
* In the signs and symptoms section, the images seem to be arranged in a disorderly fashion, maybe place them elsewhere. Also your image comparing age and intellect is extremely small. The sizing of a larger majority of your photos needs to b adjusted
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* There were only two examples of management strategies, are there anymore out there? Maybe you could do a comparisons table for this section
--[[User:Z3332629|z3332629]] 15:23, 22 September 2011 (EST)

2011 Group Project 3

2011-10-07T00:41:15Z

Z3289066:

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Links==

'''External'''

[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | [http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet]

'''Internal'''

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
----

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2011 Group Project 3

2011-10-07T00:39:52Z

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='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==Links==

'''External'''

[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia] | [http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet]

'''Internal'''

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic] | [http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
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{{2011Projects}}

Talk:2011 Group Project 3

2011-10-07T00:35:48Z

Z3289066: /* Discussion */

[[2011_Group_Project_3|'''Group 3''']]: [[User:z3289066]] | [[User:z3289301]] | [[User:z3289829]] | [[User:z3289991]]

{{2011GroupDiscussionMH}}

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_3_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_3_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

==Discussion==

Pathophysiology -

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/21655260 This ones about the psychophysiology of having an additional X chromosome

http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1111/j.1651-2227.2011.02246.x/pdf That's about the generally clinical features, with reference to pathology. It's got some good images, so I've requested permission for their use

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20014371 This one assess the differences of cognitive function of XXY and YYX patients - not sure it would be overly useful though

http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/20014369 Impact of XXY on cognitive function

I'll let you know if I find anything else

--[[User:Z3289066|Elisabeth Karsten]] 11:35, 7 October 2011 (EST)

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Haha, Dona can you see this?? Robert, Liz and I were talkingabout our group page and we thought that it may be better if we collate aetiology and pathogenesis, so there is no repetition. and then maybe add a pathophysiology section. I dont mind working on it. What do you think Dona?--[[User:Z3289829|Souti Khalil]] 12:10, 6 October 2011 (EST)

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Okay, so the page has undergone some reformatting. Hopefully this will look better, as Souti and Liz have been reorganising the content.--[[User:Z3289991|Robert Klein]] 11:30, 6 October 2011 (EST)

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Sounds good!! i will definately elaborate more in genetics and hopefull find an image to put there.
--[[User:Z3289829|Souti Khalil]] 10:25, 6 October 2011 (EST)

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I think that non-disjunction and genetics should be aetiology instead of pathogenesis. However Souti, you need to elaborate slightly more on the genetics.
--[[User:Z3289991|Robert Klein]] 10:23, 6 October 2011 (EST)

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Thanks Guys! The necessary changes to the Epidemiology have been made. See you all tomorow
--[[User:Z3289991|Robert Klein]] 15:55, 5 October 2011 (EST)

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Hey Liz, thanks, I think the history section is just about complete. I took into consideration all the peer reviews and changed a few things, however let me know if you think anything else needs to be done there. Epidemiology looks good rob!! Also, the picture in the introduction was just something that i found, but if you find a better image feel free to change it. I'll try to work on non-disjunction and aetiology later tonight. See you all tomorrow!

--[[User:Z3289829|Souti Khalil]] 13:49, 5 October 2011 (EST)

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That looks really good rob, nice work. The picture in the intro is nice, but it doesn't have a reference and we do already have an image of the Klinefelter karyotype in the Diagnosis section. I'll see if I can find something else for the intro. The timeline for history looks really good.

--[[User:Z3289066|Elisabeth Karsten]] 13:24, 5 October 2011 (EST)

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Hey Guys,
I tried to play around with an idea for epidemiology. Below is my idea. Note: I have changed nothing from Epidemiology on the main project page yet.

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]
One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.
A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.
Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.
[[File:Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png|thumb|left|Figure 3. The average intellect of boys with Klinefelter's Syndrome differs from that of normal males]]

--[[User:Z3289991|Robert Klein]] 13:40, 2 October 2011 (EST)

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I have amended the mistake in the reference list (6) since there was a citation error. There was a mistake in the original coding. --[[User:Z3289991|Robert Klein]] 13:20, 2 October 2011 (EST)

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Okay, the apropriate changes have been made to the history. I have saved the original copy on my computer of the history for future reference.--[[User:Z3289991|Robert Klein]] 07:36, 2 October 2011 (EST)

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I just got an email from Dr. Mark Hill, he prefers images from journal articles, so he'll probably remove them :( --[[User:Z3289829|Souti Khalil]] 23:17, 1 October 2011 (EST)

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2 images now, feel free to play around with them. --[[User:Z3289829|Souti Khalil]] 17:49, 1 October 2011 (EST)

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I just uploaded an image to the introduction, if you think its not appropiate or suitable there, feel free to replace it. also, let me know if their is any issue's with the copyright clearance.

--[[User:Z3289829|Souti Khalil]] 17:39, 1 October 2011 (EST)

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I think that sounds good Rob. I would also like suggest that the last two paragraphs in epidemiology moves to the signs and symptoms section, I think it would fit in a bit nicer there. Thanks Souti, did you want to do something in regards to the 'non-disjunction' sections? I was thinking we should fuse these together into one section (aetiology?), I also added all our non-disjunction pictures into the one section so it doesn't look too repetitive.

--[[User:Z3289066|Elisabeth Karsten]] 13:58, 1 October 2011 (EST)

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Hey Guys, Thanks for the nice feedback :). What I am proposing is that we replace, sorry, the long history paragraphs before the timeline with something similar to what I have written in my last comment. I will not change anything on the main project page without you guys approval first.

--[[User:Z3289991|Robert Klein]] 12:27, 1 October 2011 (EST)

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Hey guys, im also equally sorry for missing the lab on thursday. Rob, are you saying to replace the chunk of text in history with this paragraph and then maybe elaborate more in the timeline?

I'm going to work more on aetiology and history. I noticed that i have only contributed to 2 parts. So apart from looking for images and external links. Is there anything else i can do to help? any other parts you think we should add? Ill definately find a quote to add into the history.

--[[User:Z3289829|Souti Khalil]] 12:16, 1 October 2011 (EST)

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Added it where?? Do you mean added to the history, or put that instead? Because I think history has more than enough text already. That sounds good though what you've written.

--[[User:Z3289066|Elisabeth Karsten]] 11:27, 1 October 2011 (EST)

Cheers Liz! Also I went through the history and took aboard some of the critical comments that people wrote on our project wall. Leaving the timeline in place, how do you think the history section would look if we added the following:

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; gynecomastia, azoospermia, hyalinised and small testes, absent spermatogenesis, elevated levels of follicle-stimulating hormone (FSH) and hypogonadism. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>.
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient<ref name="PMID17415352"/>. This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref><pubmed> 13632697</pubmed></ref>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome<ref name="PMID3529433"/>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

--[[User:Z3289991|Robert Klein]] 11:17, 1 October 2011 (EST)

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No worries, looks good thanks rob. Yeh I went through and deleted a big chunk, but it still looks pretty long hey? I'll give that a go, thanks.
--[[User:Z3289066|Elisabeth Karsten]] 09:51, 1 October 2011 (EST)

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After reading the critique comments, I am proposing that we modify the introduction to something like:

First discovered in 1942, Klinefelter's syndrome is caused by the addition of one or more X chromosome(s) in affected males<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by gynecomastia, aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>. He depicted a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis. There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

People were suggesting that our original introduction is too long. What do you all think of this?--[[User:Z3289991|Robert Klein]] 07:19, 1 October 2011 (EST)

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Everyone,
Firstly forgive my absence from the last lab. It was Jewish New Year so happy new year to all!! Secondly, I will have another look at epidemiology, introduction and glossary and see if I can fix it up according to all the comments listed. I can get this properly done later today.
--[[User:Z3289991|Robert Klein]] 06:14, 1 October 2011 (EST)

----

Hey guys, so we're now able to fix up the page for final submission. If you haven't already gone through the peer assessment, it would be good to do that. From what has been said I've changed the intro around a bit, let me know if I should change it more. I've also fixed up the references so there are no duplications. If you see any, just make sure to fix it up. If you're not sure how to do it I can show you in lab next week, or else just let me know and I can give it a go.

I was also talking to Dona during the lab, and we were thinking that (as was mentioned in the peer assessment) we probably only need one section on Non-disjunction, I know they say different things, but it might be better to combine the sections. I feel they would fit better in aetiology, then maybe the genetics section would fit better in pathogenesis? That was just my opinion really, if you've got any other idea just let us know.

We were also thinking (from looking at the other pages) we should get more interactive things, so diagrams, images, we've probably got enough tables. But a quote or two would look nice, I thought they were a good addition on the other pages. Maybe that would fit nicely into history?

Sorry about the long message, hope it helps and we can get this fixed up. Though I think we've already got a lot of good information. I plan to add a bit to the research section regarding "Future Research", and I'll be looking for more images today.
Good luck!!

--[[User:Z3289066|Elisabeth Karsten]] 12:22, 30 September 2011 (EST)

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==Peer Review==

A great Effort can been throughout the page. Some of these comments may be helpful.
*Introduction is well researched and referenced but I reckon it’s too long for introducing the topic.
* The History needs to be more organised in a way : like each year should have a separate paragraph. It will make it easier to read.
*Aetiology is well structured, however, I noticed the image needs a reference and a source.
*The Alignment of both images in the Pathogenesis section need to be adjusted to either sides.
* images are missing from the Signs and symptoms. In the table, Puberty and adulthood seem to miss the reference of the source.
* Great work on the table “Other Similar Defects” and the glossary.
* in General, Solid work on the page, references are enough evidence. One Last comment, avoid the repetition of the references(1,3) and some others need to be re-formatted ( 35,36) z3284061

'''Group 3'''

* The introduction is a little text heavy and might need to summarised
* The timeline could be longer
* Image in the Aetiology section is lacking a copyright notice
* The links in Aetiology are good
* An image would be good in Sign and Symptoms
* Pathogenesis needs more referencing
* Some information has been repeated in more than one section
* Links to the Glossary might be useful
* Overall its a good job
--[[User:Z3292953|z3292953]] 11:10, 29 September 2011 (EST)

'''''Klinefelter's Syndrome (Group 3) Peer Review:'''''

Introduction: Information needs to gloss over the entire page a little bit more. Also, the image used has not been referenced correctly and needs to have a copyright notice and the student template.

History: Seems a bit repetitive at first glance. Would it be possible to combine all of this information into the one table? Otherwise, information is good.

Epidemiology: Information is good, however the picture on the left hand side is too small. They have been referenced well.

Aetiology: Picture in this section is slightly ambiguous. Some readers may get confused. Possible more information as to what the picture is portraying. Also, reference the picture and make sure it has a copyright notice.

Pathogenesis: Good information and great hand-drawn images. Possibly need to be slightly larger and explained further. Only 2 references in this whole section?

Signs and Symptoms: Good, succinct list. However, maybe a bit more description? Also, images seem out of place. The images need to have correct referencing format and need to contain the student template. First image is too small.

Diagnosis: Good information. Image needs proper referencing and student template.

Management: Image needs a label at the bottom. Otherwise good image.

Other Similar Defects: This section was well done!

Current Research: Good information but possibly break up the text with a picture or two.
Well done and good luck with editing! --[[User:Z3290808|z3290808]] 10:41, 29 September 2011 (EST)

Klinefelter’s Syndrome – Group 3

* I thought the introduction was very thorough however it didn’t really flow and came across as rather disjunct. Maybe you could actually be a little briefer in this section as it does contain a lot of detail that could possibly serve better in other sections. Good use of image in this section.
* Good use of the table in the history section, maybe an image in this section would look nice also. Use of bullet points as suggested by other reviewers might help to give a more succinct overview, but I thought the writing in this section served well.
* Putting both images in the Epidemiology section on the right side of the page I think would look better, also the sizing looks like they could be matched.
* Aetiology is very well written. Good use of images.
* Some of the pictures need to be referenced correctly and also a little more detail once you click on the images is needed to help explain exactly what is being shown.
* Missing pics in Signs and Symptoms table. Maybe if its hard to find some you could remove this heading from the table and just have the images offset, as then it would not look incomplete.
* Some formatting issues in diagnosis section. I liked the inclusion of the movie clip.
* Current research could be better elaborated. Good explanation of papers however it doesn’t give an overall feel of what is happening in the field. Also the inclusion of future research direction could be an important point.
* Glossary a little incomplete.

--[[User:Z3288196|Z3288196]] 10:39, 29 September 2011 (EST)

'''Peer Review'''
You need to break up the large amount of text with more tables. The amount of text is quite overwhelming up until 'Signs and Symptoms'.
Speaking of this section: The table looks FANTASTIC. Really neat, simple, love it! However... you haven't alternated the colours correctly. You need to end with light purple... you have two dark blocks next to eachother.

Your 'Action of inhibitors' picture needs to be better segregated. Put a border around it or something.

Try to keep your formatting of headings consistant. In further research, the headings do not appear in the contents, but in Diagnosis, they do.

Oh and... YOU DON'T NEED X-CHROMOSOME IN GLOSSARY. The 16yo girl sitting in this lab knows what this means...
--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:28, 29 September 2011 (EST)

Group 3:

The long introduction and history needs a pic.

The pictures in epidemiology are really small.

Links to the videos are a good idea.

There is an inconsistent amount of referencing throughout the various sections. Some sections have an excessive amount of referencing and others have just enough. Maybe 2-4 a section.

The references take up quite a bit of the page most probably because there are repeated references that have not yet been addressed.

z3332178 =]

'''Group 3:'''

*intro: the structure of this is a little confusing and it’s not really clear what you’re talking about. The flow of this section is really important – think ‘if I read it on a wiki page, would I read any further, or would I search a different page cos this was just too confusing?’ It might be good to start off your first sentence introducing the disease instead of talking about what happens in normal meiosis first. These few sentences that you put in the middle would be a good few opening sentences.. ‘One of these is known as Klinefelter's syndrome. This describes a syndrome where a person may have one or more extra X chromosomes. This is most commonly due to a process known as non-disjunction during meiosis,’ but start off with ‘Klinefelter’s syndrome is….’ But the content was good.

*history: this section was good with content and structure, but perhaps replace the second paragraph that has all the wordy dates with the timeline and stick your references there. Sometimes it works better with fewer words in a table than a chunky paragraph.

*epidemiology: making the pictures bigger would be nicer. Also theres a lot of info about stuff I would read under clinical manifestations which should be placed there instead.

*etiology: overall good section. The images were really useful. Loved the animation hyperlinks.

*patho: working on the ‘nondisjunction’ to be in one continuous line under the images would be easier to read on the viewer. Other than that, good section.

*signs and symptoms: good section. Easy to read. Concise.

*diagnostics, and the following subheadings: were all easy, well written, flow was good.

*glossary: really liked how you subheaded each part of the alphabet with the letters ‘A’, ‘B’ etc.

--[[User:Z3290558|z3290558]] 09:56, 29 September 2011 (EST)

'''Peer Review'''

:*The first paragraph is not necessary, talk about Klinefelter’s specifically not about sex chromosomes. This can be discussed further in the webpage.
:*Double spacing of paragraphs and other formatting looks awkward.
:*Great historic information but could be integrated into the timeline instead of having large paragraphs and a timeline.
:*Really liked “other similar disorders”. Great idea.
:*Some references need to be fixed so there is not double ups in the reference list.

--[[User:Z3217043|z3217043]] 08:55, 29 September 2011 (EST)

'''Peer Review'''

The wiki has overall interesting information and is well structured. You have also taken all of Mark Hill's suggestions and improved on the site a lot. Some issues:

:*Introduction is a little confusing and not very understood well. Should start off with Klinefelter’s description.

:*Some images are too small. To expand images while reading the wiki breaks up the flow, especially the table images.

:*I don't like the break-up of the alphabet letters in every title on the Glossary section; I find it very distracting.

--[[User:Z3293267|z3293267]] 08:53, 29 September 2011 (EST)

'''Peer Review'''

*Intro: Not a very good idea to introduce the disease with an overly simplified/unexciting image of meiosis, especially if you want the responder to keep reading. I’m sure there something more exciting to represent the disease.

*History: Thorough research, you just have to find a better way of representing it. Take the text, break it down and add it to the timeline. If I was given this to read I would look at the timeline and skip the text, it’s too much.

*Epidemiology: image: “Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png”. The png should not be left at the end of image and quite honestly the table is hard to understand with little explanation given. Wouldn’t people ask what is “ F(1,27= 5.9, p=0.02”? Either explain the table thoroughly or get rid of it.

*Aetiology: Animations were excellent! Perhaps use still-frames as images in this section, because the picture provided is a bit dull and looks very similar to the opening image.

*Pathogenesis: The two images look very similar; perhaps use different colours to indicate their differences. It will make the page more appealing also. The information is relative and easy to follow, although some information is overlapping with aetiology.

*Signs and symptoms: Love the table format- but more information is required. More detail on each section and corresponding images would improve it. Also there is no referencing in the “puberty” section.

*Management:“Action of Amoratase Inhibitors on Production of Estradiol.JPG” is not referenced.

*Other similar defects: It’s a lot more thorough than a few of the sections explaining the disease itself. I don’t think you need to be this descriptive in this section.

*Image/text ratio: need more interesting images (no more cell division images though), and also need to be more detailed in a few sections as mentioned above.

*Overall: Good job, but you still have some work to do.

--[[User:Z3290270|z3290270]] 02:35, 29 September 2011 (EST)

'''Group 3 Peer evaluation'''

*The introduction is good. It brief and informative of what t o expect in the page. The only criticism I have is that the historical background that was placed towards the end of the section, which should probably have been in the beginning or incorporated somewhere there.
*The History section is good, but probably too detailed. I think you can mix the timeline and history together and make this section a bit more concise.
*Epidemiology is a bit of a disappointment for me. There is a bit of information of the demographics of the disease, like prevalence, but I think epidemiology should go deeper into it, like talking about geographical distribution or if there is any race that are more inclined to developing the syndrome. Also this section ended up being an in-depth illustration of a patient’s clinical manifestation. Probably a few statistics on what percentage shows these different types of manifestation and figures some figures of the variation in mutation.
*The etiology section is very informative and I think it has all the information needed for that section. I just think that the arrangement of the information could probably be changed a bit. I think the genetics subsection is unnecessary, even though it does break the section up a bit and allows categorization of it. I just think that you could organise the ideas in this section better than what it already is. The image used here was very appropriate and aids the reader.
*I really like your pathogenesis section. It’s simple yet informative. It is very effective because the terms and concepts that you guys have here are not foreign to the reader because you have already introduced them beforehand, or explained it. Only downfall I guess is the referencing. There is only one section of your information that is referenced.
*Signs and symptoms are done well. You got away with just listing them because most of it is self-explanatory. I guess the only thing that will make this section amazing are some more elaborate images.
*Diagnosis section is done quite well, although the heading should be reconsidered to something like diagnostic test/procedure or something because the diagnosis is “klinefelter’s syndrome”. You also did a good job in incorporating what the tests are looking for, especially in the karyotyping bit. Unfortunately, this was not done for prenatal diagnosis methods, so a bit more information on this one. Finally, I don’t think the statistics need a whole subheading for it. It could just be part of an introduction to this section.
*I like the management section and the image that you used with it is used appropriately and very useful
*The other similar defects is informative, but I think that you went into far too much detail for it in a page dedicated for klinefelter’s syndrome. It is written well and the information in it are amazing though.
*I like the current research section because it says to the reader that the information on this page are up-to-date, giving the whole page credibility. What would probably make it better is a future direction kind of area, where you can put in some proposed theories or studies by researchers, and at the same time some of your own ideas of the direction where this syndrome should head into.
*I am not a big fan of glossaries, but it does look good
--[[User:Z3290841|z3290841]] 10:21, 29 September 2011 (EST)

'''Peer Review Assessment'''
*Overall, good use of sub headings and layout.
*Maybe start the introduction with the actual disease rather explaining the genetics behind it. Got a bit boring. However rest of it was well written.
*History section is well researched. Table is a good summary of the key events. Try and insert an image in this section to break up the heavy text and bring some color into the page.
*The epidemiology section contains information about clinical manifestations and appearances that can be included in a different section. Try and refine this section a little bit. Enlarge the two images in this section.
*Aetiology was well written. It might be a good idea to include some text below the student drawing included in this section explaining it. It doesn't make much sense at the moment.
*I liked the pathogenesis and sign and symptoms sections
*Liked his 'other similar defects' table. Explains the information quite well.
*Very well researched assignment.
--[[User:Z3291622|Z3291622]] 01:23, 29 September 2011 (EST)

'''Peer Review'''
* Picture under "management" is not explained.
* Introduction properly touches on all the topics elucidated later without crossing over too much.
* History is made relevant, linking it to Signs and Symptoms as well as Aetiology.
* Pathogenesis needs more references, as could Signs and Symptoms.
* The layout of Diagnosis At Birth is peculiar.
* Signs and Symptoms could use more demonstrative pictures.
* Glossary is fairly comprehensive.
* Use of related diseases section is interesting, but perhaps should be included within Diagnosis under "Differential diagnoses" or something similar....
--[[User:Z3290689|z3290689]] 00:28, 29 September 2011 (EST)

'''Peer Review for Group 3'''

*The first paragraph of the introduction could be inversed so it can actually start with what Klienfelters syndrome.
*Introduction seems a bit long, making it a bit briefer will capture the audience’s attention better.
*Within the history section the dates should be in bold so that it is easier to follow the information in this section. However, the history does give a good background to the syndrome.
*Table with major advancements is well done
*Epidemiology includes alot of information that doesn’t relate to epidemiological studies, and rather talk about clinical manifestations of people with the syndrome. Maybe put this type of information under another title.
*Figure 4 in the aetiology section should be explained more so that readers could understand what they are looking at.
*The genetics section under the aetiology is interesting, but is it necessary for it to be there, or how does that info link to Klienfelters Syndrome?
*Genetic pathogenesis is explained well. I think the two diagrams should go after the non-disjunction paragraph as it will make the page look better. Also you could talk about how this problem produces the problems for the patients throughout their life.
*Good use of table and dot points in the signs ans symptoms page. It will look good if you have a picture for all categories as you already have 2.
*In the diagnosis section, a little effort should be made to explain how karyotyping occurs as it will make that part better. Other than that the section is good
*I like the ‘other similar defects’ section as it allows the reader to compare and contrast klienfelters with other diseases
*Current research presents a picture to the reader about the current research area for klienfelters.
*Referencing MUST be fixed up as there is repetitive referencing seen in the list.

--[[User:Z3291317|Z3291317]] 23:43, 28 September 2011 (EST)

'''Group 3'''

Introduction: I think you need to explain what the disease is before you explain the genetics behind it. Also, this section seems more like a summary of the whole project. I think you could change it a bit to include more general information on the background of the disease before going into detail.

History: I think this section would be good if all the text was incorporated into the timetable and some pictures added to balance out the text.

Epidemiology: Good section overall however, the pictures could be a lot bigger.

Etiology: Good section but I think the picture needs a caption to explain what the diagram is referring to.

Pathogenesis: This section is clearly explained. The pictures are great but need to be bigger.

Signs and symptoms: The table is good but I think it would look much better if you added pictures for all the sections.

Diagnosis: Similar advice to most other sections- the text is good but I think you should add some pictures to demonstrate some of the abnormalities.

Management: The picture would be good with a caption to explain what the diagram means.

Defects: The table is good but a couple of the pictures are far too small.

Current research: Good section, but again, needs some pictures!
--[[User:Z3291324|z3291324]] 23:20, 28 September 2011 (EST)

Group 3

Hi, overall, a nice project page with interesting information.

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: Nice introduction, good flow and easy to read. However, image needs proper information and perhaps 'This disorder was first described by Harry F.' could be placed earlier on in the intro rather than in the middle
#* History: Nice section, very interesting
#* Epidemiology: First paragraph is good, but I feel the rest of this section doesn't quite belong here, such as the information on seizures, IQs, diagnosis. This section should focus on stats (sex/birth/ethnic/demographic/etc). Fig 2, 3 belong more in the signs and symptoms
#* Etiology: the '1:1000 male' contradicts the '1:500' given in epidemiology. Fig4 needs coyright information
#* Pathogenesis: Needs better referencing, also placing fig 5, 6 on either side doesn't look too good with the text. Perhaps place them below one another?
#* Signs: Seems a bit incomplete, it'll also be good to explain the image of 'pubertal gynecomastia'
#* Diagnosis: Sentence structure could be improved, ie. 'performed because physicians may suspect it because of clinical findings'. Information is interesting, but could be presented more clearly, perhaps in a table?
#* Similar defects: very nice, presented well with good information, easy to read
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Good images used with a nice range of self drawn images. However, lot of the images need to be formatted properly with required information
#Content is correctly cited and referenced.
#* overall referencing was well done, except pathogenesis needs more referencing
#The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* Nice range of references used
#Relates the topic and content of the Wiki entry to learning aims of embryology.
#Clearly reflects on editing/feedback from group peers and articulates how the Wiki could be improved (or not) based on peer comments/feedback. Demonstrates an ability to review own work when criticised in an open edited wiki format. Reflects on what was learned from the process of editing a peer's wiki.
#Evaluates own performance and that of group peers to give a rounded summary of this wiki process in terms of group effort and achievement.
#The content of the wiki should demonstrate to the reader that your group has researched adequately on this topic and covered the key areas necessary to inform your peers in their learning.
#* The information is there, but maybe from now til final assessment, you could do further research in all sections, as they do seem a little short.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* better page layout
* glossary: sorry, but I feel the alphabet subheadings here are not very effective as you have it in alphabetical order anyway

--[[User:Z3291643|z3291643]] 22:01, 28 September 2011 (EST)

'''Group 3:'''

•Good subheading structure, the page flows nicely

•Some parts of the introduction need to be reworded and it should start with an explanation of Klinefelter’s rather than the description of meiosis which is i think is unnecessary at the very beginning of the page.

•Detailed history in the text section, however is the timeline finished? Research after 1970 needs to be completed.

•Glossary needs to be completed, and i’m not sure if you need the separate headings for each letter in the glossary as it spreads it all out a lot.

•Lots of the references are repeated

--[[User:Z3332183|z3332183]] 21:25, 28 September 2011 (EST)

'''Peer Assessment Group 3 Klinefelter's Syndrome'''
*Your introduction is interesting and a good summary of the page
*The history is good however could use a picture
*The images under 'Epidemiology' have quite poor resolution, can hardly read them
*The rest of the page looks great and I have no more to add.
*It is easy to read, well balanced text and pictures and informative
--[[User:Z3308968|Tahmina Lata]] 20:54, 28 September 2011 (EST)

'''Group 3: Peer Assessment'''
* You have constructed an informative page about an interesting syndrome
* At this stage it's a little text heavy, so may be you can cut it down and add some pictures instead
* In the history section it would be great to see these dates from the table with the text blended in, so it's on chronologic flow.
* You seem to take it very serious with the mitosis or not communicating with each other because you have four pictures of mitosis in three different sections. One picture and a good explanation would be sufficient. Then you could use the rest of the space for other pictures.
* The table for signs ad symptoms is great, but looks a bid empty. So may be you can change the format or add some more pictures.
* May be you could write a bid more about therapeutic options. I would find that more important then "similar abnormalities"
* Good referencing through the section. Just change the "double referencing"
* Overall, you page has a lot of information, may be you can balance it a little more out, communicate so you don't have "double" information and a few more pictures would be great.
--z3279511 17:08, 28 September 2011 (EST)

'''GROUP 3 Peer Assessment: Klinefelter's Syndrome'''
*I feel that the introduction is too lengthy, it should be summarised a little more. Although the info is informative, its structure needs some work- grammar and punctuation should be reviewed and sentence structure could be improved
*Figure 1 could use a more descriptive legend
*Historical information is ok, maybe could be improved by extending the timeline to a more resent years, also an image wouldn't hurt, just to break up the text a little
*epidemiology could use some proof reading to correct minor grammar mistakes e.g. "Males born with Klinefelter syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes", sentence structure could also be reviewed so this section flows better (some sentences are short, but other than this, this section is informative
*Incidence is repeated twice, maybe could stick to one section, and it's different in each section (1 in 50 000 or 1 of every 1000 male births?)
*Aetiology (don't really know what this means), and the subheading "genetics" could be a better choice for the whole section, but info here is informative and understandable
*I do like the links made in Aetiology, the picture in this section could use a better legend and needs to be referenced properly (no copyright statement?)
*There is overlapping info in the Aetiology and Pathogenesis sections (both have Non-disjunction as subheading), and both have the same sort of images
*Table in signs and symptoms is too small should be a lot bigger so detail can be seen, it also needs to be referenced properly
*The info for signs and symptoms is good in a table, but it would be better if the table had colour so the reader can distinguish each section of the table
*diagnosis is informative

Overall:
*Reference list needs some work, some of the references have been repeated
*Project could be improved by finalising the glossary and maybe linking the words in the body to the glossary itself
*Images need to be referenced properly and some need more informative legends
*I feel some of the information is a little repetitive, maybe could read through and edit so it flows better
*subheadings and headings could be reviewed and re-organised so page flows better
*I do like the feature of links added throughout, maybe more would make it better

--[[User:Z3331556|z3331556]] 14:28, 28 September 2011 (EST)

'''Group 3 Peer Assessment'''
* Try to link your sentences in general - at times the reading is quite disjunct and difficult to read. Try to rewrite sections and see if it can be written in a more succinct manner.
* In general, keep the images on the right hand side of the page - I know you want to break things up, but if images are kept on the left then it disrupts the paragraph lining and makes the information difficult to track with the eye (just a minor thing, this is my opinion anyway)
* Some subsections just appear too short; is it really necessary to make a subsection for one or two sentences, as is the case of karyotyping? Try to implement all of the information into one paragraph
* The first image requires a proper reference to the work; is there any copyright information? And also protect your hand-drawn images - they are drawn excellently, but have no copyright information (unless you are happy with the images been used straight away by other students! :) )
* The current research section and possible treatment options section is far too brief; if this is a syndrome that causes many problems, then there should be a fair amount describing our direction of research and methods in which we can combat this syndrome. Try to find more information here!
* Overall, a good balance of the images and format, but reconsider the structure of paragraphs and subheadings so that the entire project has a better feel. Many sections feel like they have been started with great enthusiasm, but this has burnt out over time, giving the project a feel that some sections are just left incomplete. Try to fix this!
--[[User:Z3288827|Leonard Tiong]] 09:37, 28 September 2011 (EST)

'''Peer Assessment'''
*The first two paras of the introduction belongs in the genetics/etiology section. Need a broad intro to the actual syndrome and what happens in it. You don’t need to give a brief overview of all the sections, this isn’t an English essay.
*History- break up with bullet points?
*Figure 3 is a bit small – a bigger pic will look better I think
*Pictures in the Pathogenesis section look funny with the text – maybe have one under the other? It just squares the text in the middle and it looks odd.
*Don’t forget the missing pics in the signs and symptoms table
*History/timeline table might look better in purple – keep it consistent with the others.
*In the Current Research section, the 2nd paper that you have described is written with very colloquial language – can’t use that here! Maybe have a brief intro para about current research and where its headed etc, not just a description of papers. Also, maybe link them to other papers, e.g. This paper shows similar results to _______, surely there are similar findings in particular areas of research?
*Fertility picture needs to be in a ‘Figure’ box with a description and explanation of what it means.
--[[User:Z3332824|z3332824]] 23:30, 27 September 2011 (EST)

'''Group 3'''

*I think the introduction should be a little more concise
*History could work better if all the information was summarised in a table/timeline rather than having paragraphs then a timeline. *Also, I find it a little hard to believe that no findings have been made since the 1970s.
*Epidemiology would probably benefit with subheadings
*Signs and symptoms are nicely set out
*I like that you have added a comparison of other diseases
*Maybe add a few more researches from 2011 rather than 2010 (if possible)
*Overall, quite a good project with some minor adjustments needed

Group 3:

*Whilst I appreciate the introduction and its content, I feel an introduction doesn’t need to be of the same size as some of the other sections of the project. It is to give a mere idea of the condition.
*History could be broken apart with dot points or bolded dates instead. How about a picture of Harry Klinefelter?
*Aetiology picture has no link to the article or where it was found, and no copyright notice.
*Pathogenesis has very little references, surely more would have been used.
*Images in table are blank and a lot more references would have been used than shown.
*space out the subheadings so they don’t look disjointed in diagnosis.
* references have not been listed properly (various links for same article)
--[[User:Z3291423|z3291423]] 18:09, 27 September 2011 (EST)

Group 3: Klinefelter’s Syndrome
*overall look: inconsistent formatting, imbalance of text and images in some sections, appropriate headings used.
*introduction: very broad, maybe too much detail?
*history is well researched; I really like the timeline at the end which summarises the major advancements. But it is very short and ends in the 1970s. It could include current research/advancements.
*Epidemiology: could benefit from a few subheadings or breaks in the text.
*Aetiology: I really like the use of external links.
*Signs and symptoms: works well in a table format but not sure why some cells are coloured and others are not.
*Other similar defects: interesting addition to the webpage, allows audience to continue research. Also demonstrates extensive knowledge of the syndrome. Great idea!
*Minor adjustment: just for convenience, glossary terms could be linked
--[[User:Z3332327|z3332327]] 16:14, 27 September 2011 (EST)

'''Group 3 assessment:'''
*Introduction begins in a confusing manner should begin explaining the disorder Klinefelter’s syndrome before explaining the genetic component of meiosis. Where the image was explained though would be more beneficial if the introduction have an image of the founder of the syndrome within this section or within the history heading.
*History has clear structure with explained information of the progress with relation to the timeline of the syndrome, images would have been more useful within this sub heading to make livelier instead or too much text.
*Epidemiology detains the male component though could explain female areas related to syndrome as well figure 3 .
*Pathogenesis is organised with images placed in areas which bring upon confusion where fig 5 and 6 both linking to Non-disjunction, image placement beneath text would be better placement.
*Signs and symptoms could have a little more elaboration and/or more images
*Sub heading of diagnosis at birth needs to place either in the centre or down 1 sentenced to become more organised.
*References should remove any repeats and the links below should be manually added to the references either under another subheading or normally
*Glossary should be linked throughout, either linking the word to the glossary or even bolding the terms so no confusion for people without any background in the area can understand.
z3332250 23:43, 26 September 2011 (EST)

Group 3 Peer Review

*Well structured and organised
*Timeline seems odd that it ends at 1970? If further information cannot be found, try to present this in a different way
*Figure 2 and 3 could perhaps be a little bigger
*Should a copyright statement be included in some of the images?
*Signs and symptoms table is great
*Some duplication of information throughout page-unnecessary
*Video link is a nice extra
*Well balanced text, images, and tables/graphs
*Overall, a well written page and visually appealing
--[[User:Z3308965|Fleur McGregor]] 18:48, 26 September 2011 (EST)

===Comments on Group Project 3===

Group 3

*Introduction seems a bit wayward to begin with. Maybe introduce the syndrome first and then briefly explain meiosis, it just seems a bit indirect. I like how the intro touches on some aspects to be described later in the page but, good work.
*History section could be organised a bit better I think, the combination of text and timeline is good but there must be a balance, right now there’s a big block of text and a teeny timeline
*People might have already said this but I think the epidemiology section is too broad and covers topics outside of its section (clinically diagnosed characteristics and such)
*Aetiology – I definitely like this section, the image is perfect and relates to the non-disjunction paragraph, information provided here is clear and easy to understand.
*Pathogenesis – maybe consider reformatting the images so that the information under ‘Anaphase Lagging’ is easier to read, and the heading ‘Nondisjunctiom’ is not in the middle, would add to continuity and the flow of the entire page if all headings were aligned to one side
*Other Similar Defects – this table is really hard to read, but the information is good, although it does need to be referenced properly
*Nice glossary and current research headings, I don’t really see anything to fix. Good job guys.

--[[User:Z3331469|z3331469]] 06:58, 29 September 2011 (EST)

'''Strengths:'''
*Smooth flow between headings and subheadings throughout the page.
*Timeline included provides a good summary of the block of text above it. Gives a reader a choice to read the summarised timeline or the block of text containing more details.
*The video links under Aetiology/Non-disjunction is very appropriate.
*The overall formatting of the page is well-done and neat.
'''Weaknesses:'''
*Introduction is a little bit too detailed. It should clear but concise.
*There is a lot of duplication of references.
*Some of the images did not include copyright statement which allows wiki users to re-use the image e.g. Figure 1
'''Specific corrections:'''
*What is aetiology?
*”These are anaphase lagging and nondisjunction. The latter of the two, nondisjunction, takes place more often.” Any statistics for this? If there is, it will be good to include it.
*Some of the signs and symptoms are not referenced.

--Z3389806 07:08, 26 September 2011 (EST)

'''Group 3'''

*Introducton: the beginning is a bit to abrupt, very nice image, otherwise good content

*History: very detailed information, useful timeline

*Epdidemiology: fig.3 would look better on the right side, the content is good

*Aetiology: no copyright information for the image, good use of subheadings.

*Pathodenesis: again, figure would look better on the right side, it disrupts the flow.

*Signs and symptoms: good table, the images look a little lost though, so maybe place them on the right edge, “age and intellect” could be bigger.

*Diagnosis: well done

*Management: good content, nice flow

*Similar defects: good content, but the structure could be better, maybe place the content in a table without the dots. Everything that belongs to e.g XO should start at the same hight

*Research: interesting section, well done

*Glossary: seems incomplete

*Make sure to include the copyright notice in all images
--[[User:Z3387190|Z3387190]] 12:13, 25 September 2011 (EST)

Group 3
* The first thing I noticed is that the project is very text heavy. Also- there are 4 images of mitosis. Is this really necessary? One is enough and you can use the other spaces to put other images in
* The introduction gives a nice, broad overview of the project. I understand immediately what is going to be said. But is there not an image of a patient to put here to draw the reader in? Maybe its just me that isn’t very excited about images of mitosis sorry.
* The history section would work better as a list of dates and names rather than a bulk of text
* Has there been no research since the 1970s? More recent findings need to be added to the history
* The epidemiology is very interesting- but there is a lot of clinical manifestations here that are described later. There is a double up in information.
* Signs and symptoms works well in a table- but more images of the condition would make it even better
* The comparison of other conditions is excellent! Great idea.
* Your information is there is just needs to be organised a little better and the fact that you have double ups on information and pictures indicates that there may not be any communication in the team- either that or laziness to find a different picture. Look forward to seeing your final project!

'''Group 3'''
* Good over all structure with the use of headings and sub headings. A very interesting syndrome and the page is easy to read.
* I think the intro could be condensed a little, as it should get straight to the point.
* I enjoyed reading the history section and good use of table and summary of history.
* I like figure 1, very nice that it was done by a student!
* figure 4 Maternal Non-Disjunction.. Is this a student drawn pic or did you use it from somewhere.. a little unclear.
* I was nice to see sign and symptoms tabulated, which made this section very easy to read and understand. good use of picture here. Could you find anymore relating to the signs and symptoms?
* I liked the addition of a movie link.
* The sub heading of diagnosis were very appropriate.
* Other Similar Defects- very interesting to add this in..
* Interesting current research: nice that it has been summarised.
* Make sure your reference list hasn't doubled up.
* Just for clarity it might be nice to use the same colour table throughout the page.
* It was good to see some of your pictures correctly labelled.

*'''Introduction''': Content is good, but it's a bit strange to start the introduction with an explanation about meiosis. Of course you need to include it, but generally one expects a few general sentences about the condition itself first, and then an explanation how problems in meiosis lead to it. Including a figure is good, but maybe put this one under the genetics section, and have a picture of somebody affected by the syndrome here instead?
*'''History''': It is one very long text, followed by a summary table under timeline. Maybe come up with a mix of the two, and make it one section? Would make keeping an overview easier. Keep the table, but put all the longer explanations you've written out under history into the table, next to the corresponding date? Content is good.
*'''Epidemiology''': Good, interesting content. The figures nicely break down the text. Well done!
*'''Aetiology''': Slight contradiction here - previously prevalance was said to be 1 in 500, now 1 in 1000? Also, you refer to Figure 1 which is all the way on top of the page - it would be nice to keep it closer to the text, in the relevant section itself. You might want to mention that MI = meiosis I and MII = meiosis II. I was also slightly surprised that you used the word "synapse" when talking about what happens between the homologous chromosomes - I might just never have come across it before (though I have taken quite a few genetics classes), but maybe double-check that? As far as I know it's called crossing over - that's what forms the chiasmata. In general, your whole explanation is very incomplete, you might wanna revise that. I know what you're trying to get at, but I don't think it's very clear for someone who doesn't have a genetics background. Also, I have a majour problem with Figure 4 - the way you illustrate it, I first thought you were showing two different chromosomes, say chromosome 1 & 2, of which there are two copies present each. Cause this is how it is pictured most of the time. Your explanation under the figure made me realise that it wasn't the case, but a) you need to improve that legend and explain more, and b) I'd strongly suggest you modify your figure so that the chromosomes look more like "X"ses - that'll make it much easier to understand that you're talking about one chromosome type, and are showing the sister chromatids and not separate chromosomes. I hope this makes sense?
The genetics part is good though.
*'''Pathogenesis''': Why does this section contain the subsection nondysjunction again? Nice, brief explanation of anaphase lagging. The nondysjunction section, unsurprisingly, mainly repeats what has already been said before. Your figures need a legend and more explanations. What are the different colours supposed to depict? Maternal vs paternal chromosomes? You need to point out that it's the size difference that shows chrom 1 vs chrom 2. Cause I thought first the colours mean homologous chromosomes, which then wouldn't be right cause it's the homologous chromosomes that align etc. Also, I'd suggest not talking about cells having three chromosomes instead of two, cause in reality, cells have so many more pairs of chromosomes than 2, instead maybe just say, 1 cell contains both of the homologous chromosomes instead of just one at the end of MI. You seem to be depicting a recombination event in Figure 6 - why? Does it have any relevance to this part? There's no mention of it in the text. Sorry this sounds terribly critical - good effort though!
*'''Signs & Symptoms''': Maybe explain more, and not just include a list with bullet points?
*'''Diagnosis''': Put the "featured imagine" right next to where it is mentionned? Otherwise seems fine to me.
*'''Management''': Looks good.
*'''Similar Defects''': Maybe rename it Syndromes instead of Defects? I was confused for a second that you were going to talk about further defects that affect KS patients, instead of similar diseases. Otherwise, looking good.
*'''Current research''': Nice long explanations of the research, though there surely are more than 3 current papers about this out there?
*'''Glossary''': How do we know which words from the sections can be found in the glossary? More terms could also be included.
*'''References''': Needs fixing. One and the same reference appears multiple times in the list.

'''Peer Assessment: Group Project 3'''
*The introduction is informative, however I think that the small paragraphs at the end detract from the section as a whole. It would be better to integrate these more so that they flow on from the previous text.
*The history section provides both detailed information and a timeline, which makes the historical stages easy to comprehend and refer back to.
*Is the image in the section on aetiology drawn by a student? If not, then copyright information and referencing needs to be included.
*In the section on diagnostic procedures, the image could be placed on the right for ease of reading.
*The figure in the signs and symptoms section and the figures in the epidemiology section are too small.
*Using colour borders in the signs and symptoms table would make it a bit clearer.
*The links to animations and a movie are great uses of additional material.
*Under the information in some of the images you have uploaded, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*The references should not be duplicated and can instead be linked together using the 'multiple instances on a page' editing guidelines: http://embryology.med.unsw.edu.au/embryology/index.php?title=References#Multiple_Instances_on_Page.
--[[User:Z3217345|z3217345]] 13:28, 27 September 2011 (EST)

'''Group 3 Assessment'''
*The Meiotic Non-disjunction jpg doesn’t have the proper citing or information about future referencing abilities.
*In the history section, I like how the occurances are both described in detail and set forth in an easy to read table format. Very organized.
*In the Aetiology section, where is the referencing for the Non-disjunction videos? Is video copyrighted?
*The Aetiology section and Pathogenesis sections seem to contain almost identical information. Are both necessary, or could they be combined/ one deleted?
*If you decide to keep the Non-disjunction videos, are the pictures in the Pathogenesis section necessary? Or do they just become redundant?
*In the Epidemiology section, both pictures need to be enlarged; they are so small I can’t make a distinction as to what’s on them.
*Signs and Symptoms- This section overall looks very good as far as information goes. The only thing I would suggest is to separate the different age sections a little bit more; their symptoms look to be running together from group to group. Also, try increasing the picture sizes, as they (especially the first one) is difficult to read.
*Again, for the video under Karyotyping, where is the referencing and copyright information on this?
*Action of Amoratase picture- This still needs to have the disclosure statement reguarding re-use and copyright guidelines. Also needs a descriptor sentence below the picture.
*Glossary- Shouldn’t there be references for these definitions?
*Both the Similar Defects and Research sections seem decent. Only suggestions:

-Similar defects chart: Try bigger pictures and sentences of less length.

-Research- Try adding a picture to the section to make it more aesthetically appealing
*Some of the references are repetitive. Make sure to fix this so they all link to a single reference instead of numerous ones of the same resource.
--[[User:Z3391078|Ashley Smith]] 14:00, 27 September 2011 (EST)

'''Group 3:'''
* The introduction is very lengthy, some parts feel as though they would be more appropriate in other sections. The image here fits nicely with the text but it could benefit from a more descriptive legend and needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>.
* In the history, you begin to use the short hand “KS” without an initially stating that this is the abbreviation for “Klinefelters syndrome (KS)”. The dates that are mentioned are very detailed although it ends in 1970, were there any other breakthroughs since then? A picture of Klinefelter would be a nice touch here.
* Epidemiology requires some proof reading as there are a couple of little mistakes and the images would have more of an impact if they were slightly larger.
* I like how you have linked figure 1 to the non-disjunction sub-heading under aetiology. The image in this section could benefit from a coloured legend, ie. Instead of saying “Blue circles are male cells”, in a box include an actual blue circle = male cells along with the other descriptions. It also needs to be properly cited.
* There is too much repetition between pathogenesis and aetiology, maybe discussion between these two students is needed to minimise repetition. Good hand drawn images but you need to include the student template as mentioned previously.
* Signs and symptoms would look better in a coloured table and with more images. I don’t think it is necessary to repeat the image comparing age and intellect here.
* Diagnosis; nice use of another form of media – a video. The abbreviation of KS in this section needs to be established first by placing KS after the first time you mention Klinefelters syndrome.
* Management is very concise and thorough
* Other similar defects; nice touch, it could look more appealing with the use of colour and larger images though.
* Current research is formatted nicely and flows well

'''Group 3 - Peer assessment'''

*The introduction is abit lengthy and choppy because some paragraphs are just 1-2 sentences. Maybe try to connect them into one paragraph and try to make it flow better.
*The history was quite informative maybe put the timeline at the top and the text at the bottom and maybe try to add more recent dates.
*Epidemiology - the use of figures are good and it is explained well in the text
*Aetiology - good idea in external linking images! the information is easy to easy as it is well structured
*Signs and Symptoms - the table is abit confusing to read, althought the information is well reduced
*Other Similar Defects - maybe the use of lines within the table would be better to separate the columns and rows because it is abit hard to read

--[[User:Z3330313|z3330313]] 19:50, 28 September 2011 (EST)

--z3290815 15:54, 28 September 2011 (EST)

'''Peer Review'''

* a lot of writing and so makes the wikipage interesting to read
* the image in the pathogenesis section needs fixing
* the image layout is not organised well
* needed to explain Klinefelter's disorder in simple terms. I could understand it but if it was explained in a more simple way it would be much better.

--[[User:Z3060621|z3060621]] 20:58, 28 September 2011 (EST)

'''Group 3'''
'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are present.

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Under aetiology, it might be good to add a sentence or two about the cause of Klinefelter's Syndrome rather than just jump right into aneuploidy. I understand that it is the aetoilogical agent in Klinfelter's but indicating it as a cause would be good to kinda give the reader a 'flag'. It is not necessary to add the information about aneuploidy in the introduction as i think you could move that section down to a more appropriate part. If need be, just mention aneuploidy as a cause in the introduction rather than dedicate the first paragraph to it in the intro.

'''*Content is correctly cited and referenced.'''
Maternal Non-Disjunction.PNG needs some references, Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG, Pubertal gynecomastia.jpg, Immunoglobulin levels in 15 girls with Turner Syndrome.png and Karyogram of male with 47, XYY Syndrome.png needs to be correctly referenced. duplication of references need to be fixed. More references need to be included when there is a huge chunk of text or it looks very much like you got everything from one source only.

'''*The wiki has an element of teaching at a peer level using the student's own innovative diagrams, tables or figures and/or using interesting examples or explanations.'''
Good drawings - explanations are understandable.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
There is a significant reference list but not enough in-text referencing.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
A lot of content on genetic problems, maybe put something in about development of embryo (if applicable)?

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has shown development and editing to be based on the above guidelines although some smaller details could be fixed.

--z3329495 21:11, 28 September 2011 (EST)

==Discussion==

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Hey i have been looking for a profile pic for some time and none have come up. So prob better if you don't look for it because I am afraid that you will waste time. Nice! birthday cake :) I should do that for my dad's bday which is coming up.
Anyways see you tomorrow
--[[User:Z3289301|Dona Cho]] 23:55, 21 September 2011 (EST)

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Hey Dona, thats a good idea! i like all the pics that you have added, and pathogenesis looks good! I just baked my dad a birthday cake and planning on doing some work on this now. So i will probably be up for a while. I am also looking for pics of H. Klinefelter. Good work!--[[User:Z3289829|Souti Khalil]] 21:12, 21 September 2011 (EST)
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I am looking for a profile picture of Mr Klinefelter. I think it will be good to put one in in the introduction section. I am having trouble finding any - but you do come across one pls put one up -I think it will look great!
--[[User:Z3289301|Dona Cho]] 20:19, 21 September 2011 (EST)

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Guys I thought that it would look good if all the images were order 'figure 1, figure2...'
Just so that it all looks uniform
Hope your ok with it but if you don't like it you can just change it back.

--[[User:Z3289301|Dona Cho]] 17:52, 21 September 2011 (EST) :)

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That looks interesting, but I'm not really up to adding any of that tonight. Feel free to add whatever you like.
--[[User:Z3289066|Elisabeth Karsten]] 22:57, 14 September 2011 (EST)

Hi guys ;)

I was just reading some stuff - found some interesting info related to management (I think it is liz?)

The part of the review is as follows:

'Decreased energy and libido, which are associated with postpubertal testosterone deficit, improve with hormone therapy and often are accompanied by improved confidence and sense of well-being.Androgen therapy should be started when there is direct laboratory evidence of a testosterone deficit or when hypergonadotrophism, which suggests such a deficit, is present. This may occur by the time the patient begins middle school...

Because gynecomastia predisposes men to breast cancer—the frequency of breast cancer is 20 to 50 times greater than in men who do not have Klinefelter syndrome1,2—monthly breast self-examination should be encouraged. If necessary for cosmetic reasons, gynecomastia may be treated surgically.'

The review also mentioned something about 'cryopreservation' so that the precious sperm can be stored and used for later IVF.

If the above sound interesting, it might be good reading the review article (particularly the management section. Follow the link below for the review.

http://www.aafp.org/afp/2005/1201/p2259.pdf

ps. I dont think I will be sleeping much tonight!!

--[[User:Z3289301|Dona Cho]] 22:32, 14 September 2011 (EST)

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I don't think we can use those pictures, unfortunately. Safest to stick with papers and hand-drawn I think. The timeline looks really really good. If anything, I would be inclined to put a bit less info in the main bit of history and focus on that time line. I think it's a nice visual respresentation of the information.
--[[User:Z3289066|Elisabeth Karsten]] 21:17, 14 September 2011 (EST)

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I found this website which has alot of picture's of KS, and there are only a few copyright statements, can we use them? [http://carregwenimages.com/klinefelters-syndrome-pictures]

Haha, I just saw them! thanks for that! I just edited the history and the timeline. Is the information in the timeline just repetitive of what i have written, should i just remove it? --[[User:Z3289829|Souti Khalil]] 20:09, 14 September 2011 (EST)
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It did end up happy in the end lol. Yeh they look really good. We're allowed to add links to our page, so I think that'd be best. I'll put those on now. Thanks!
--[[User:Z3289066|Elisabeth Karsten]] 18:46, 14 September 2011 (EST)

Thanks for fixing up the table in signs and symptoms, it looks great!

That video was mean, i was eating when i watched it and i felt so sorry for the little boy, i couldnt watch the rest. :(

If you think we need an animation i found these two websites, but i have no idea of how we would put them on to our page.

[[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm]]
[[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm]]
--[[User:Z3289829|Souti Khalil]] 18:09, 14 September 2011 (EST)

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That video is so funny! I was laughing to the point of tears while watching this! I don't think Dr. Hill would be too happy if we added the video to our webpage though. Great job Liz once again with the editing. Keep up the good work!--[[User:Z3289991|Robert Klein]] 15:22, 14 September 2011 (EST)

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Hey everyone, I just uploaded our 1 Wikipedia image. It's the karyotype of Klinefelter's syndrome. If anyone founds anything better on Wiki, just make sure you say something and take that one off.
--[[User:Z3289066|Elisabeth Karsten]] 09:52, 14 September 2011 (EST)

So I found this video, it's super cute and lame. But I think it's a nice representation? Not sure how applicable it is though... http://www.youtube.com/watch?v=6q2JxMDaNys
--[[User:Z3289066|Elisabeth Karsten]] 10:08, 14 September 2011 (EST)
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[[File: Signs and Symptoms by Age Group.PNG|right|300px| Signs and Symptoms by Age Group.PNG|thumb]]

Thanks Liz! I really loved the intro and the picture that you created! Maybe we don’t have to remove it, however I will also be on the lookout for a picture which may better suit the introduction. In the meantime, I was thinking maybe we should order the subsections better, for example; Introduction, History, Epidemiology, Aetiology, Pathogenesis, Signs and symptoms, diagnosis, management, other similar defects and then current research. I just think we should explain the cause and pathogenesis of the disease before the signs and symptoms and diagnosis.

Lastly, I found a table on a website and have created a similar one on signs and symptoms. I'll just upload it here, and we can decide if we want to use it.

That is all. --[[User:Z3289829|Souti Khalil]] 13:13, 12 September 2011 (EST)

That table looks really really good, though it could be easier if we upload it like the other table I put up, as opposed to a picture. I'm happy to do that if you like. And yeh that order looks good too, I'll change it now and if anyone disagrees they can change it back. --[[User:Z3289066|Elisabeth Karsten]] 22:29, 12 September 2011 (EST)
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Our page is starting to looking really good!! I just fixed up the aetiology, it may need more work to be done though. Liz the picture i made, is really similar to the one you have in the introduction, is it too much?? Sorry about the delay in uploading it. --[[User:Z3289829|Souti Khalil]] 00:50, 12 September 2011 (EST)

That's fine, I kind of expected that. You use it since it fits in with your topic and I'll do another one for the intro. Aetiology looks really good, nice work!

--[[User:Z3289066|Elisabeth Karsten]] 09:07, 12 September 2011 (EST)

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Hey Liz, Great job with the editing! It looks really good. I will keep on the lookout for gathering more information. --[[User:Z3289991|Robert Klein]] 20:31, 11 September 2011 (EST)

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Hey everyone, I've just fiddled with the formatting of the page a bit. If you don't like it, of course feel free to change. I also changed the formatting of the table t make it a bit clearer to read, if you preferred the old one though I've saved a copy of it so just let me know. Just looking at the page, some things in epidemiology I think would fit a bit better in signs and symptoms; and eitiology and pathogenesis are a little repetive of each other which I guess we should of expected. But we'll be able to discuss it properly on this coming thursday.

--[[User:Z3289066|Elisabeth Karsten]] 20:24, 11 September 2011 (EST)

To help out a bit, I found some links to articles that are 'Open Access'. This should save time for you guys:
http://www.springerlink.com/content/g68408vq74752421/fulltext.pdf
http://psy.hull.ac.uk/Staff/t.jellema/VantWout_PlosONE.pdf
http://www.autismresearchcentre.com/docs/papers/2011_BCetal_Plos%20biology_unsolvedmystery.pdf
http://www.ojrd.com/content/pdf/1750-1172-5-15.pdf
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020292
http://www.hogrefe.nl/fileadmin/user_upload/Documenten/PDF/Wetenschappelijk_onderzoek/Bruining_et_al_-_Dissecting_clinical_heterogeneity_of_ASD_through_genotypes.pdf
http://www.ijponline.net/content/36/1/36

Hope this helps!--[[User:Z3289991|Robert Klein]] 12:23, 9 September 2011 (EST)

Looks good, thanks rob.

--[[User:Z3289066|Elisabeth Karsten]] 20:24, 11 September 2011 (EST)

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I had to remove the photo from 'signs and symptoms so that I can confirm it's copyright restrictions. Sorry about that. --[[User:Z3289991|Robert Klein]] 07:44, 9 September 2011 (EST)

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I edited the Epidemiology and fixed it up as best I could. As well, I found and added a picture to the signs and symptoms section to make it a little clearer. I still seem to be having difficulties with formatting. If anyone comes across charts that I can use for Epidemiology, that would be much appreciated. I still can't find anything that I can use. I will fix up the 'other similar defects' section and have it ready very soon. --[[User:Z3289991|Robert Klein]] 06:39, 9 September 2011 (EST)

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Hey guys, sorry I've been a bit MIA recently. But yeh I agree totally, I was planning to finish off the intro once everything else is finished, but for the moment I'll make sure I'll finish off my other sections.
And yeh you're ideas re:tables and diagrams sounds great. I'll have a go at drawing a couple on paint as well
--[[User:Z3289066|Elisabeth Karsten]] 21:39, 8 September 2011 (EST)

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Good idea Souti! As well as that, I will retype my sections and try and fix them according to what Dr.Hill wishes. Maybe for treatments, you could speak about the drugs used to manage the condition. We do need to edit the other sections and add much more content and diagrams. Perhaps a few handrawn diagrams wouldn't go astray?--[[User:Z3289991|Robert Klein]] 18:40, 8 September 2011 (EST)

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Hey guys, I noticed earlier today that Mark Hill has put comments on our page that we need to change and improve. So i'm going to take out 'case study', and replace it with 'treatments'. What do you guys think? Make sure you have a look at what he has said.
--[[User:Z3289829|Souti Khalil]] 17:44, 8 September 2011 (EST)

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Rob, 'Other Similar Defects' is looking great! I am committing the next couple of hours to Klinefelter's syndrome. Do you guys think we could elaborate a bit more in the introduction, just to give a larger scope of our disease?

--[[User:Z3289829|Souti Khalil]] 11:48, 8 September 2011 (EST)

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I added images to 'Other Similar Defects'--[[User:Z3289991|Robert Klein]] 07:55, 7 September 2011 (EST)

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I have constructed a table for Other similar defects! I think that it should be alright, however there may not be enough info so the conditions may not properly be explained. We are still waiting on a table for signs and symptoms as well as a diagram for pathogenesis--[[User:Z3289991|Robert Klein]] 10:01, 6 September 2011 (EST)

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What we should do is add a table to 'similar defects', a diagram for pathogenesis, a and a table for signs and symptoms--[[User:Z3289991|Robert Klein]] 12:49, 1 September 2011 (EST)

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Glossary, Epidemiology and Similar defects have all been added. Let me know if anything else needs to be done!--[[User:Z3289991|Robert Klein]] 06:04, 1 September 2011 (EST)

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Alright Everyone,
For the different genotypes dotpoint, I will cover that when I complete the section to do with 'similar defects'. I have fixed up the referencing system. --[[User:Z3289991|Robert Klein]] 13:53, 27 August 2011 (EST)

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Hey guys,
I have included a list of things that Mark Hill emphasised in regards to our group project in the lab today;

- Different genotypes

- Animal models

- Review articles

- Importance of how the disease comes about (pathogenesis).

So, by next Thursday our main page should have plenty of content under each subheading. 
--[[User:Z3289829|Souti Khalil]] 14:14, 25 August 2011 (EST)

----

Hey Guys,
I have added a discussion tab for any enquires and updates on the progress of our assessment, as well as a referencing tab (or whatever they are actually called) at the bottom of the page. So for each section, if anyone finds relevant articles/images etc. they can place it there.
Oh, and please remember to add new content to the top.
--[[User:Z3289829|Souti Khalil]] 00:53, 18 August 2011 (EST)

----

Hey Guys,
Sorry to be a bother. I am having trouble referemcing properly in the Wiki format, as what can be seen in my Epidemiology piece and also my messing up of the reference list. Would one of you mind showing me how to fix this problem? Thanks so much and I will have the piece on 'other similar defects' prepared by Saturday. The glossary will be uploaded on Monday.
--[[User:Z3289991|Robert Klein]] 05:40, 18 August 2011 (EST)

----

'''Referencing'''
PMID is the reference number that you need

without the ':' will act as an link to the article
--[[User:Z3289301|Dona Cho]] 12:51, 25 August 2011 (EST)

==References==

If you find any good papers relating to someone elses topic, you can put them under these subheadings to help out.

Hey guys! this is a publication which seem to be pretty good!!

http://www.nichd.nih.gov/publications/pubs/klinefelter.cfm
--[[User:Z3289301|Dona Cho]] 12:54, 25 August 2011 (EST)

===Description/Introduction===

===History===

Natural history of seminiferous tubule degeneration in Klinefelter syndrome<ref><pubmed>16172111</pubmed></ref>

===Signs and Symptoms===

===Epidemiology===

Abramsky L, Chapple J.47, XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling. Prenat Diagn. 1997;17:363–368.

Bojesen A, Juul S, Gravholt CH.Prenatal and postnatal prevalence of Klinefelter syndrome: anational registry study. J Clin Endocrinol Metab. 2003;88:622–626

[http://www.aafp.org/afp/2005/1201/p2259.pdf Klinefelter Syndrome]

===Diagnosis===

Hey guys, it's Dona. I put my name down for this section. I will try to get mine done by the end of this week. :)

--[[User:Z3289301|Dona Cho]] 17:23, 24 August 2011 (EST)

===Treatment===

===Etiology===

===Pathogenesis===

===Case Study===

===Similar Defects===

===Current Research===
http://www.ncbi.nlm.nih.gov/pubmed/7446531
Check this out!!--[[User:Z3289991|Robert Klein]] 05:03, 1 September 2011 (EST)

<ref><pubmed>21342258</pubmed></ref>

===References===
<references/>

==Pictures==
[[File:Magnetic Resonance of Head MRI from patient with Down Syndrome and Klinefelter's Syndrome.jpg|thumb|Magnetic Resonance of Head MRI from patient with Down Syndrome and Klinefelter's Syndrome]]

--[[User:Z3289829|Souti Khalil]] 23:57, 17 August 2011 (EST)

[[File:Klinefelter's Syndrome.jpg|thumb|center|Klinefelter's Syndrome]]

--[[User:Z3289066|Elisabeth Karsten]] 23:31, 13 August 2011 (EST)

[[File:Overview of human testicular sample from a patient with Klinefelter's syndrome.png|thumb|center|Klinefelter's Syndrome patient testicular sample]]

--[[User:Z3289991|Robert Klein]] 10:17, 16 August 2011 (EST)

[[File:Kleinfelter syndrome.jpg|thumb|center|Facial dysmorphic features in a child with double aneuploidy—Down syndrome and Klinefelter syndrome]]

--[[User:Z3289301|Dona Cho]] 20:35, 17 August 2011 (EST)

==Topic Choice==

Hey guys, so after having a look at that list I quite like the sound of
*Anencephaly or
*Klinefelter's syndrome

There's loads of resources for Klinefelter's syndrome, but I think Anencephaly sounds really interesting. It's a type of neural tube defect, so we may even be able to do that as a topic - neural tube defects (it's on the list as well).
Just let us know what you think, thanks guys!

I've just attached a review for each

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

[http://www.ncbi.nlm.nih.gov/pubmed/21110233 Neural Tube Defects] or [http://www.ncbi.nlm.nih.gov/pubmed/17089587 Anencephaly]

--[[User:Z3289066|z3289066]] 09:32, 6 August 2011 (EST)

Hey Everyone,
I am leaning towards Klinefelter syndrome as it seemed interesting to learn about. I found a couple of articles on the internet which explore more the epidemiology of the condition amongst the population. Liz, I read through your artiles and they were quite interesting in the way that they explored the genetics behind the condition. We will be able to perhaps link these in with the epidemiology to make our argument more convincing.

Below is a review article:

[http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/(SICI)1097-0223(199909)19:9%3C808::AID-PD637%3E3.0.CO;2-B/pdf]

The Research Article:

[http://jcem.endojournals.org/content/88/2/622.full.pdf+html]

Both articles explore more the epidemiology of klinefelter's syndrome as I felt that it would be interesting to look at its prevalence, and frequency of distribution within a population. The first review article that I hasve linked to explores the frequency of Klinefelter's syndrome in a population along with various other genetic anomalies.

--[[User:Z3289991|z3289991]] 07:02, 9 August 2011 (EST)

Yeh that sounds good to me, if anyone has any objections just let us know. We can figure out exactly what we want in the page on thursday, but yeh should def's talk about the epidemiology.

--[[User:Z3289066|z3289066]] 14:53, 9 August 2011 (EST)

Hey guys!

I think that Klinefelter's syndrome is definitely an interesting disease and it has lots of resources. I think we still need a plan B though, a few other diseases which I thought were really interesting are;
- Thalassaemia
- Anencephaly (good pick Liz!)
- Spina Bifida
I found a really good review article on Klinefelter’s syndrome, although it’s pretty dated.
[http://archinte.ama-assn.org.wwwproxy0.library.unsw.edu.au/cgi/content/full/158/12/1309]
[http://onlinelibrary.wiley.com.wwwproxy0.library.unsw.edu.au/doi/10.1002/ajmg.b.30163/pdf]

I shall see you all thursday!

--[[User:Z3289829|z3289829]] 22:15, 9 August 2011 (EST)

Hey guys, this is dona - I guess I am the last one to write on the board (sorry!)

I personally like the topic; neural tube defects. Reasons are 1. there is so much information because it is an umbrella term that includes many conditions like spina bifida and anencephaly
and 2. we will be learning the developing of the neural tube next week in lecture - so it will not be difficult to understand the etiology of neural tube defects

Here are the links:

review article [http://www.ncbi.nlm.nih.gov/pubmed/10899792]

research article [http://www.tandfonline.com.wwwproxy0.library.unsw.edu.au/doi/pdf/10.1080/19485565.1991.9988793]

p.s Hey could everyone identify themself by writing their name before writing on this discussion forum, that way people know whose talking. (please)

--[[User:Z3289301|Z3289301]] 17:23, 10 August 2011 (EST)

===Sections===

*Description/Introduction - Liz
*History - Souti
*Signs and Symptoms - Dona
*Epidemiology - Rob
*Treatment - Liz
*Eitology - Souti
*Pathogenesis - Dona
*Similar defects - Rob

I was thinking it'd be good to also do a topic on recent research, I'm happy to do that one, and should also do a glossary. So we should have someone finalise that, but it'd be really helpful if everyone could just add words in they think would be good as you go. Does anyone want to volunteer for editing that? Just put your name in the spot below so everyone knows.

*Recent research - Liz
*Glossary - Rob
*Diagnosis - Dona
*Case Study - Souti

--[[User:Z3289066|Elisabeth Karsten]] 12:15, 13 August 2011 (EST)

----

Hey Guys,
I have uploaded an image to the Epidemiology section of the Group webpage, however it appears to have distorted the whole webpage in that all the other categories below epidemiology have been pushed to the side. Also, I am having trouble trying to enlarge the image. Do you know how I can fix this problem? The table was referenced appropriately.
Cheers

--[[User:Z3289991|z3289991]] 10:14, 13 August 2011 (EST)

Hey, yeh that should be fine for the moment, don't worry too much about the formatting. You can fix it, but it'll be easier to do once there's text there too move around it.
There should be a page explaining all the details about picture formatting, but I can't qutie remember how to do it off the top of my head. Is that the size of the original image? Because that could be part of the problem.

--[[User:Z3289066|Elisabeth Karsten]] 12:09, 13 August 2011 (EST)

Oh I've just realised what's happened, see how you've put the file name then "thumb"? The default for thumb is to make it slightly smaller and move to the right where it will wrap around whatever text is there. You can try [File name|thumb|left|name] if you want it on the left, or else instead of 'left' you can say 'center'. But it's gotta be 'center', not 'centre' (I think). Or else you don't have to use thumb at all, and just leave it out completely.

Hope this helps.

--[[User:Z3289066|Elisabeth Karsten]] 14:02, 13 August 2011 (EST)

Thanks Liz,
You know what? I will add some text during next week and then play around with the formatting. You are right in your first comment, because that way I can format the picture and text properly. Thanks so much for your help though.
--[[User:Z3289991|Robert Klein]] 15:21, 13 August 2011 (EST)

----
==Peer Assessments==

* Great amount of depth, you have covered each subheading quite well
* It was great to see a comparison to other similar defects
* Non-disjunction is discussed twice, can it be summarised into just the one section?
* In the signs and symptoms section, the images seem to be arranged in a disorderly fashion, maybe place them elsewhere. Also your image comparing age and intellect is extremely small. The sizing of a larger majority of your photos needs to b adjusted
* You’re referencing needs to be tidied up; there are multiple entries from the same source that tends to clutter your reference section.
* There were only two examples of management strategies, are there anymore out there? Maybe you could do a comparisons table for this section
--[[User:Z3332629|z3332629]] 15:23, 22 September 2011 (EST)

2011 Group Project 3

2011-10-06T23:29:52Z

Z3289066: /* Related Links */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

----
==External Links==
[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia]

[http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet]

==Internal Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T23:28:51Z

Z3289066: /* External Links */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

----
==External Links==
[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME Andrology Australia]

[http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf Information booklet]

==Related Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T23:28:06Z

Z3289066: /* External Links */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

----
==External Links==
[http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME|Andrology Australia]

[http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf|Information booklet]

==Related Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T10:58:59Z

Z3289066: /* Current Research */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

----
==External Links==
Andrology Australia: http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME

Information booklet: http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf

==Related Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T10:57:54Z

Z3289066: /* Current Research */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px| Figure 2: Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown in [[Media:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|Figure 2]].
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

[[File:FMRI Images of Brain Activation in XXY Patients.JPG|fMRI Images of Brain Activation in XXY Patients|thumb|300px]]

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

----
==External Links==
Andrology Australia: http://www.andrologyaustralia.org/pageContent.asp?pageCode=KLINEFELTERSSYNDROME

Information booklet: http://www.apeg.org.au/Portals/0/resources/hormones%20&%20me%20klinefelter%20syndrome%20may%202011.pdf

==Related Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
----

{{2011Projects}}

File:FMRI Images of Brain Activation in XXY Patients.JPG

2011-10-06T10:53:33Z

Z3289066: This image shows area's of activation in the brain after certain stimuli. Within the control, activation (the coloured portion) was present when the subject showed signs of distrust when looking at faces. Interestingly, in the XXY patients, there was no

This image shows area's of activation in the brain after certain stimuli. Within the control, activation (the coloured portion) was present when the subject showed signs of distrust when looking at faces. Interestingly, in the XXY patients, there was no activation here. Suggests neural developmental differences in increased X chromosomal dosage.

===References===
<pubmed>21737434</pubmed>

Copyright - Permission was granted for the non-commercial use of the content.
"This is a License Agreement between Elisabeth Karsten ("You") and Oxford University Press ("Oxford University Press"). The license consists of your order details, the terms and conditions provided by Oxford University Press, and the payment terms and conditions."

{{Template:2011 Student Image}}

User:Z3289066

2011-10-06T01:27:37Z

Z3289066:

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Eleven==

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

User:Z3289066

2011-10-06T01:27:12Z

Z3289066: /* Lab Attendance */

{{2011Student}}

=Lab Attendance=
--[[User:Z3289066|Z3289066]] 12:21, 28 July 2011 (EST)

--[[User:Z3289066|z3289066]] 12:53, 4 August 2011 (EST)

--[[User:Z3289066|z3289066]] 11:09, 11 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:28, 18 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:07, 25 August 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:11, 1 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:08, 15 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 11:01, 22 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 10:59, 29 September 2011 (EST)

--[[User:Z3289066|Elisabeth Karsten]] 12:27, 6 October 2011 (EST)

=Labs=

==Lab One==
''Identify the origin of In Vitro Fertilization and the 2010 nobel prize winner associated with this technique.''

The first incidence of ''in vitro'' fertilization was in 1978 by Edwards RG. et al. who then received the nobel prize for his work in 2010. Since then, work in ''in vitro'' fertilisation has extended into Assisted Reproductive Technologies (ART) which now incorporates 17 different techniques.

''Identify a recent paper on fertilisation and describe its key findings.''

This paper refers to research concerning sperm chemotoxis and it's 'journey' to the oocyte and consequential fertilisation. It describes the selective process involved in fertilisation and the potential of the involvement of fluid shear in this selection.<ref><pubmed>21788487</pubmed></ref>

''Identify 2 congenital anomalies.''

*Dandy–Walker syndrome - This is a congential brain malformation which is associated with the partial or complete absence of part of the brain, often involving the cerebellum.
*Amniotic band syndrome - This involves the constriction of the limbs by the amniotic band potentially resulting in swelling of limbs, constriction or amputation.

==Lab Two==

''Identify the zona pellucida protein that spermatozoa binds and how is this changed (altered) after fertilization.''

The sperm binds to the receptor Zona Pellucida Protein 3 (ZP3) on the zona pellucida which is surrounding the oocyte. This is necessary for entry into the oocyte, and thus fertilisation. After fertilisation, the membrane is depolarised as a primary block to polyspermy. The IP3 pathway is activated, leading to an increase in intraceullar calcium and altering ZP3, so that it will no longer binds sperm to the membrane and acting as another block to polyspermy.

''Identify a review and a research article related to your group topic. (Paste on both group discussion page with signature and on your own page)''

[http://www.ncbi.nlm.nih.gov/pubmed/21397196 Klinefelter Syndrome]

==Lab Three==

''What is the maternal dietary requirement for late neural development?''

Folate is essential for late neural development. Its use has been associated with a decrease in neural tube defects. These defects include spina bifida which results from a lack of neural tube closure, or anencephaly which is the result of a lack of cranial neural tube closure.

''Upload a picture relating to you group project.''

[[File:Klinefelter's Syndrome.jpg|thumb|center|Average IQ of people suffering from Klinefelter's Syndrome]]<ref><pubmed>21655260</pubmed></ref>

==Lab Four==

''The allantois, identified in the placental cord, is continuous with what anatomical structure?''

The allantois is continuous with the hind gut (and endoderm) of the embryo.

''Identify the 3 vascular shunts, and their location, in the embryonic circulation.''

*Ductus venosus - this is situated between the umbilical view and inferior vena cava
*Ductus arteriosus - this is situated between the pulmonary artery and the descending aorta
*Foramen ovale - this is situated between the right and left artium

''Identify the Group project sub-section that you will be researching. (Add to project page and your individual assessment page)''

*Introduction
*Treatment/Management
*Current Research

==Lab Five==

''Which side (L/R) is most common for diaphragmatic hernia and why?''

The left side is most common (90%) for diaphragmatic hernia's to occur. This is due to uneven diaphragm closure during embryonic development. The left side of the diaphragm tends to close after the right side, and so the risk of herniation here is much greater.

==Lab Six==
''What week of development do the palatal shelves fuse?''

The palatal shelves fuse during week 9, this is also known as fusion of the secondary palate.

''What early animal model helped elucidate the neural crest origin and migration of neural crest cells?''

Quail-chick chimeras were used in the 1980s to investigate neural crest migration, this utilised the differences in the nucleoli of chicks and quails.

'''What abnormality results from neural crest not migrating into the cardiac outflow tract? ''

This is known as a 'Tetralogy of Fallot', this can result in truncation of the outflow tract, or even its complete abscence.

==Lab Seven==
''Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy?''

''(a)'' It seems that satellite cells are ''not'' necessary for muscle hypertrophy. It was shown that satellite cell-depleted muscle could still undergo hypertrophy. After 2 weeks, it showed the same increase in muscle mass, in satellite cell positive muscle and satellite cell depleted muscle. <ref><pubmed>21828094</pubmed></ref>

''(b)'' Satellite cells are necessary for new fiber formation and regeneration. In normal muscle, satellite cells definitely contribute to the process of hypertrophy, it is just not necessary. <ref><pubmed>21828094</pubmed></ref>

''Why does chronic low frequency stimulation cause a fast to slow fibre type shift?''

This type shift has been associated with an increase in myoneuclear content and satellite cell activiation. The use of chronic low frequency stimulation causes a change in the oxygen and metabolite need of the muscle fibres. Fast fibres tend to be glycolytic and thus do not have the capacity for oxygen metabolism. The result of this need is an alteration in structure and type (ie from fast to slow) where the formed slow fibres are able to withstand this chronic activation. The fast to slow fibre type shift is acheived by the "neighbour rule" ie move from Type IIB (fast) to IIA to IIX to I (slow).

''Trisomy 21 Critique''

*I quite like the incorporated links that take you directly to the glossary, nice effect.
*The list of links at the end of the introduction doesn’t flow very nicely. I like the idea, but maybe if you move them to the top of the page or even the bottom it would fit better.
*The introduction could do with a bit more information and correspondence to the rest of the project.
*The section “Some Recent Findings” would probably be better just titled “Recent Findings”, it sounds more professional. This section would also fit better at the end of the page after we know all the details of the disorder. It is too difficult to jump straight into these specifics. Also, it is a good idea, but instead of using direct quotes from the paper, a succinct summary of the research would be better. That way you could refer back to the entire page.
*How does karyotyping work?
*Can you elaborate on the section “associated abnormalities”? The setting is a little confusing, what disorders are you referring to? Why are they similar? Or are these a list of signs and symptoms? If so, why are they associated with the addition of an extra chromosome 21?
*Instead of linking to the glossary, why not try to incorporate some of this information into the text?
*Interesting information, but some of these topics can be incorporated together, ie “limb defects” and “heart defects”. Or else, add more information in each, it looks a little sparse.
*There is no copyright information on the picture of ‘John Langdon Down’.
*I like the idea of prevalence, this is important to give perspective to the disorder, but a more worldwide distribution would be good instead of just Ireland and USA.
*The table in “screening” looks really good, but another column or something describing the screening techniques and details involved would be really good. The information in “novel screening strategies” sounds interesting but there needs to be more.
*Interesting diagram for SNP screening.
*“Screening by country” really should reference a few more countries than just spain.
*A glossary situated directly on the page would be good, as opposed to some links to an outside glossary, and other terms defined in text ie in the “aneuploidy” section.
*The topic and a lot of the work sounds very interesting and has the potential for a fantastic project, just a bit more content and better structured sub-headings needs to added and revised.

==Lab Eight==

''Peer Review''

'''Turner Syndrome'''

*Just make sure you’re consistent with the capital letters for Turner syndrome, you’ve got ‘Turner syndrome’, ‘turner syndrome’ and ‘Turner Syndrome’ throughout the page
*The page looks good, just a bit of final rearrangement of the images would be even better
*You’ve got a lot of good information in "Clinical Manifestations" but perhaps the information would look better in a table as opposed a long list? Some pictures wouldn’t go astray either
*I like the links down to the glossary, it makes it very efficient
*The table in "Diagnosis" looks really good, but try to shrink the pictures in it down a bit so it’s not so huge
*It would be good to expand some of the sections in “Treatment”, you’ve got a really good basis but you need more than one line in “Speech” etc
*Your "Research" is very detailed with lots of good papers
*Overall it is quite a good page, it just needs a little bit of reformatting

'''DiGeorge Syndrome'''

*The page has a really nice setout, the introduction and history looks really good. It has a nice flow.
*There could be at least one other picture in 'Epidemiology' and 'Etiology', otherwise it just looks like a big block of text
*The second last paragraph in 'Epidemiology' would be better suited in 'Clinical Manifestations'
*There's a bit of repetition between 'Etiology' and 'Pathology', it could be better to combine these
*The 'Diagnostic Tests' look really good, fantastic table and images
*I love the ultrasound picture
*The table in 'Clinical Manifestations' is really great with lots of detail
*I understand it's difficult to find, but more images in 'Clinical Manifestations' to give a visual representation would be fantastic
*"Teratoogy of Fallot as ''an'' example...."
*"Once diagnosed, there is no single therapy plan. Opposite, each patient needs to be considered individually and consult various specialists" This doesn't make muhc sense, that was from the 'Treatment' section.
*You had a lot of good information in 'Current and Future Research', but I found myself getting lost in all the text. Maybe subheadings would help?
*Don't forget to fix up the references, we don't want to see webpages as a reference even if it leads you to the paper
*Overall your page looks very good, some minor formatting would be useful

'''Huntington's Disease'''

*The intro and history look really good, I like the timeline and the quote box
*What year was the information in the table in 'Epidemiology' sourced? Because from looking at the references, it seems to be within a 20yr period. Is this enitrely accurate to compare these?
*What are HTT and HD halotypes (in 'Epidemiology')? You've only put 'halotypes' in the glossary, you also need to a give a brief definition within the text, not just glossary
*Nice image in 'Genetics', lots of good easy to understand information there as well
*You need to fix the file under 'Role in Transcription Inhibition'
*The diagnosis section looks really good, make sure you get rid of that subheading for the video though
*Interesting table in 'Treatment', however the section on 'Tetrabenazine' does not has complete sentences and seems a bit unnecessary. Honestly I don't really care how the drug works (ie receptors) I'm more interesting in it's implications regarding HD
*The 'Therapies' section was good and succinct
*Current/Future Research looks really good
*Overall the page isn't bad, just need to confirm some details to improve it ie dates and definitions

'''Fragile X Syndrome'''

*You need a bit more in your introduction. Introduce the basics before jumping straight into the methylation of specific genes etc. Try to describe what CGC triplet is, what methylation is, on what chromosome is FMR1 gene on? You need to spell some of this stuff out to begin with
*The table in 'History' looks good, there is a nice outline of dates there
*Nice diagram in 'Epidemiology', it's a really good illustration
*'Etiology' can you do a brief explanation of what "amplification" implies
*There is a lot of good information in 'Signs and Symptoms', but it's lost in a block of text. It would be good if you broke it up with some images of clinical symptoms or something
*How do the diagnostic tests work? Why are they used? What are the benefits and diadvantages of them? This section needs to be filled out a bit
*Clearly a lot of work has gone into 'Treatment'
*'Recent Research' is structured nicely, makes it a lot easier to read
*There's more than 8 words that require a definition
*There's clearly a lot of good information in the project, but there is a lot of detail and it needs to be broken up a bit. Though, overall it is not a bad project

'''Tetralogy of Fallot'''

*An image in the 'Introduction' to introduce the topic would not go astray
*"...Infants turning blue when crying..." middle of sentence, no capital is required. What is tet spells?
*History might work better as a timeline, otherwise at least '''bold''' the dates so I know whats going on
*Surgical history has been covered through most of 'Contemporary History', there's not a whole lot of point having two subheadings here
*The 'Epidemiology' is a bit sparce? Are there no other stats to add to this section?
*There is a lot of good in information in 'Genetics', but I think you need something to break it up, you've got the images of the chromosomes (which are very good), but can you find other images? Maybe put some of the information into a table?
*The 'Abnormalities' section looks really good. The information is clear, succinct, with good illustrative images
*Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Diagnosis is poor, it isn't referenced and clearly isn't finished ("insert text here"). This does not flow on from the rest of the page at all. It looks a bit dry with no colour or images
*There are minimal references in 'Treatment', surely you didn't all that information out of only a few papers?
*I like the table in 'Treatment'
*Can you make the subheadings in 'Treatment' as actually subheadings as opposed to just bold?
*It's coming along, but you need more images! It starts off well, but there aren't many toward the end.
*Make sure you finish the project off!

'''Angelman Syndrome'''

*You need to add an image in 'Introduction' or 'History', something to get the reader interested
*You kind of repeat yourself in 'History'. Try putting more information into the timeline, as opposed to the text.
*Epidemiology' looks a bit bare, is there a graph you can add or something? Also a bit more information can't hurt
*Pathogenesis is HUGE, looks like you've put a lot of work into it. But, it needs to be broken up a bit. Also, shrink that first image down, it's a bit out of place. Maybe try to use proper subheadings to break it up, not just bold. Are you able to make a table out of 'Animal Models'? Ie type (mice), advantages, disadvantages, diagram (if present).
*In 'Signs and Symptoms', you don't need the "Adapted from" you can just reference that. Or at least move it out of the table. I got confused and thought they were meant to be some of the symptoms
*But you've got some good information in the rest of the section, nicely arranged with the images
*Try shrinking the flow chart in 'Diagnosis', also reference it. It you made it yourself, say so
*Nice table for 'Treatments'
*Can you give a bit of an introduction to the table in 'Genetic Counselling', don't just jump straight into it
*Make sure you reference that first paragraph in 'Current Research', you can't just make statements without justifying them with articles
*Quite a good project, just need some more images and a bit of formatting

'''Friedreich's Ataxia'''

*Where did the contents go?
*Try splitting the introduction up into a few paragraphs as opposed to just the one
*Is there ''nothing'' else to put in history? What you've got is good, but i'm interested in seeing a bit more
*'Atiology' looks good, there seems to be quite a bit of work gone into it. But how are there no references for 'Inheritance'
*Split your paragraphs up a bit more in 'Neuropathy', at the moment it is quite difficult to read
*Can you try to include all of the signs and symptoms into a table? It's a bit difficult to read when you list the in text; though the table already present looks really good
*Diagnosis looks fantastic, very nicely set out and lots of interesting information
*Try to get a picture for either 'Diagnosis' or 'Treatment'. The bottom half of the page looks a bit bare
*Can you expand 'Current Research' a bit, explain what and how they do the research etc
*No glossary?
*The page looks quite good, you've clearly got a lot of information there, just need to make it a bit easier to read

'''Williams-Beuren Syndrome'''

*'Introduction' is good, but need an image to open up the page
*Can you try to compile all that text in 'History' into the timeline? Otherwise it's a bit much and a bit repetitive; an image couldn't hurt either
*Good work with 'Genetics', easy to read and interesting
*Diagnosis might fit better below the signs and symptoms, ie after we know enough about the syndrome to fully appreciate the diagnosis
*'Treatment' doesn't really fit in 'Epidemiology', again this would be better towards the end of the page
*Nice table for 'Phenotype of Williams Syndrome', very clear and informative
*Your subtitles are a little confusing, you might want to try incorporating all the condions ie cardiac and genitinary into one section
*Though the information within these sections is very good
*You seem to be missing a ''lot'' of images, it's difficult to read when it's just blocks of text
*For 'Cognitive, Behavioural and Neurological Phenotype' you need more references. You should back up what your saying with at least 2 references; though there seems to be a lot of interesting information here
*'Structural Differences in Brain' - only 1 reference for all that information? That doesn't seem very reliable
*I like the topic 'Specialised Facilities and Supportive Associations', really interesting choice. Very good
*For 'Current Research', instead of just an article reference, make a brief summary of the paper and describe why it is significant? Otherwise this section is a bit pointless.
*The glossary can't hurt to be expanded..... and finished.
*Overall, the page looks good, clearly a lot of research has gone into it. Just focus on making it more visually appealing, and work on those references

'''Duchenne Muscular Dystrophy'''

*Make sure you add a proper heading for the page, so it doesn't just start with 'Introduction'
*The 'Introduction' is a good start to the page, very easy to read and understand
*'History' is a bit difficult to read, try to make is sequential order, or at least '''bold''' the dates
*In 'History' we don't really want a story, but key dates in the history of the discovery of the disorder. Surely something has happened in the past 150 years?
*Good work with 'Pathogenesis', it is a good description of the development of the disorder
*Can we see an image relating to the signs and symptoms?
*'Clinical Manifestations' is a good thorough description, though I don't understand what going on with the last section 'Smooth Muscle' with the random '''&&&'''. It is also a whole lot more general than the preceeding sections. Is it finished?
*Could you give a bit more detail in 'Diagnosis'. It would be good to explain each method a bit more and explain why they are relevant.
*Can you expand on the table a bit? ie P188, what exactly is it used for? How does it treat it? How effective is it? When is it administered etc
*No current research section? This could be a good conclusion to the page - the 'Stem Cell Transplant' section from 'Treatments' would fit better here
*The glossary needs to be finished and expanded on
*Overall the page is not bad, but more images are needed and some clarification on topic

'''Cleft Palate and Lip'''

*Your introduction needs to be ''seriously'' expanded. What exactly is it? Defining features? Anything?
*'History' could be expanded on a bit, but the timeline looks good. Try to take the spaces out between each date of the timeline, at the moment it's a bit unneccesarily long
*'Diagnosis' would fit better towards the end of the page closer to treatment. It is a bit hard to understand before we've even had a proper description of the disorder and clinical symptoms
*Though the information in 'Diagnosis' is quite good, the table is also quite interesting
*'Syndromes and Anomalies Associated with Cleft', title should fixed up 'Associated Syndromes and Anomalies' sound better. It also needs to be finised!
*There's not even a single reference in 'Atiology'
*'Developmental Staging' are you refering to Carnegie stages? If so, say so.
*Reference!! And finish 'Pathophysiology'. You won't get the marks for just saying 'it will be done soon', think of the rest of your group
*There is not a ''single'' reference in 'Genetic Configuruation', so where then did you get your information? This section also needs images, and a bit of formating. There isn't much consistency in the use of captial letters for 'Cleft Lip'. Either use it or don't, "seems to be related to the cause of Cleft palate and cleft lip incidence" and throughout the page aswell
*For 'Treatment' and 'Complications' a table would be good. It is not very visually appealing as a long list. That way you can incorporate some more information as well.
*'Problems Associated with Cleft Palate' would be better positioned higher up in the page. How do you know what your treating if you don't even know the associated problems. Reference!
*'Current and Future Research' really needs to be expanded. There is no where near enough information here
*The page is coming along, but it really needs to be finished, there are far too many gaps, and no where near enough references. Try reading multiple papers before adding information.

==Lab Nine==

==Lab Ten==

==Lab Eleven==

=References=
<references/>

--[[User:S8600021|Mark Hill]] 00:40, 30 July 2011 (EST) Well done, you do remember some of cell biology online work. Since you have completed this online work before, perhaps you will also be able to help the students new to this format.

2011 Group Project 3

2011-10-06T00:35:28Z

Z3289066: /* Epidemiology */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Risk factors for male breast cancer.JPG|Risk factors associated with male breast cancer|thumb|left]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==Associated Internal Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
----

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2011 Group Project 3

2011-10-06T00:34:27Z

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='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|300px|Risk factors associated with male breast cancer|thumb|left]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==Associated Internal Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T00:33:21Z

Z3289066: /* Associated Internal Links */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|300px|Risk factors associated with male breast cancer|thumb|left]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==Associated Internal Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development Genital Development]

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T00:32:12Z

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{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|300px|Risk factors associated with male breast cancer|thumb|left]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==Associated Internal Links==

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Oocyte_Development|Oocyte Development]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=2010_BGD_Practical_3_-_Gametogenesis|Gametogenesis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Cell_Division_-_Meiosis|Cell Division - Meiosis]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Abnormal_Development_-_Genetic|Abnormal Development - Genetic]

[http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Genital_Development|Genital Development]

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T00:26:45Z

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{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|300px|Risk factors associated with male breast cancer|thumb|left]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
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='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|300px|Risk factors associated with male breast cancer|thumb|left]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T00:25:15Z

Z3289066: /* Klinefelter's Syndrome */

{{2011ProjectsMH}}

='''Klinefelter's Syndrome'''=

__TOC__

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|300px|Risk factors associated with male breast cancer|thumb|left]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T00:23:40Z

Z3289066: /* Epidemiology */

='''Klinefelter's Syndrome'''=

__TOC__
{{2011ProjectsMH}}

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|300px|Risk factors associated with male breast cancer|thumb|left]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-06T00:21:50Z

Z3289066: /* Epidemiology */

='''Klinefelter's Syndrome'''=

__TOC__
{{2011ProjectsMH}}

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|200px|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

[[File:Risk factors for male breast cancer.JPG|300px|Risk factors associated with male breast cancer|thumb]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

--[[User:S8600021|Mark Hill]] 00:25, 15 September 2011 (EST) You need to fix your referencing so that multiple entries for the same reference are not listed here (see ref 18 which I have amended in the text).

<references/>
----

{{2011Projects}}

File:Risk factors for male breast cancer.JPG

2011-10-06T00:18:27Z

Z3289066: This table illustrates the major risk factors associated with male breast cancer. Of note, people with Klinefelter's syndrome are 50x more likely to get male breast cancer. ===References=== <pubmed>20463819</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/ar

This table illustrates the major risk factors associated with male breast cancer. Of note, people with Klinefelter's syndrome are 50x more likely to get male breast cancer.

===References===
<pubmed>20463819</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866553 PMC2866553]

Copyright - This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

2011 Group Project 3

2011-10-05T22:38:03Z

Z3289066: /* Introduction */

{{2011ProjectsMH}}

=Klinefelter's Syndrome=

--[[User:S8600021|Mark Hill]] 14:36, 8 September 2011 (EST) Good sub-heading structure and overall draft text layout. Some sections very content poor, who was working on Diagnosis and Current Research? In particular where are all the figures???

* Introduction- you have the content there, but it reads very poorly in structure. You should try and fix this. Remember the introduction is the first thing that people will read. Also good to have some figure to interest the reader. There are also lots of clinical terms that may not be understood by the average undergraduate student.
* History - There are only 3 worthy features in the history of this disease? You have not done the work here. This should perhaps also be structured as a timeline, bullets date first in bold.
* Epidemiology - read the first sentence, its not English. The next section also is not very clear. I think this whole section should be looked at again in terms of structure and clarity.
* Signs and Symptoms - this should illustrate some of these Signs and Symptoms, not the genital features please.
* Diagnosis - OK this is sort of a description for Karyotyping, but it is not complete or accurate description of the method. Look it up please and fix this.
* Etiology - this is not a description of [[#Glossary | '''non-disjunction''']], which is what this section should be about.
* Pathogenesis - first sentence is repetition of previous sections, this should have been fixed by now so that the same content does not appear in multiple sub-headings.
* Case Study- I don't think you need this section.
* Other Similar Defects -first identify why they are similar, then explain how you will describe in a table.
* Current Research - very poor. Who in the group should have done this section?

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"><pubmed>21397196</pudmed></ref>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png|thumb|left|Figure 3. The average intellect of boys with Klinefelter's Syndrome differs from that of normal males]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|right|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

--[[User:S8600021|Mark Hill]] 00:25, 15 September 2011 (EST) You need to fix your referencing so that multiple entries for the same reference are not listed here (see ref 18 which I have amended in the text).

<references/>
----

{{2011Projects}}

2011 Group Project 3

2011-10-05T06:51:09Z

Z3289066: /* Epidemiology */

{{2011ProjectsMH}}

=Klinefelter's Syndrome=

--[[User:S8600021|Mark Hill]] 14:36, 8 September 2011 (EST) Good sub-heading structure and overall draft text layout. Some sections very content poor, who was working on Diagnosis and Current Research? In particular where are all the figures???

* Introduction- you have the content there, but it reads very poorly in structure. You should try and fix this. Remember the introduction is the first thing that people will read. Also good to have some figure to interest the reader. There are also lots of clinical terms that may not be understood by the average undergraduate student.
* History - There are only 3 worthy features in the history of this disease? You have not done the work here. This should perhaps also be structured as a timeline, bullets date first in bold.
* Epidemiology - read the first sentence, its not English. The next section also is not very clear. I think this whole section should be looked at again in terms of structure and clarity.
* Signs and Symptoms - this should illustrate some of these Signs and Symptoms, not the genital features please.
* Diagnosis - OK this is sort of a description for Karyotyping, but it is not complete or accurate description of the method. Look it up please and fix this.
* Etiology - this is not a description of [[#Glossary | '''non-disjunction''']], which is what this section should be about.
* Pathogenesis - first sentence is repetition of previous sections, this should have been fixed by now so that the same content does not appear in multiple sub-headings.
* Case Study- I don't think you need this section.
* Other Similar Defects -first identify why they are similar, then explain how you will describe in a table.
* Current Research - very poor. Who in the group should have done this section?

==Introduction==

[[File:47,XXY Klinefelter's Syndrome.jpg|thumb|right|220px|47,XXY Klinefelter's Syndrome]]

Klinefelter's syndrome, first described in 1942 by Harry F. Klinefelter<ref>Klinefelter HF, Reifenstein EC & Albright F. '''Syndrome characterized by [[#Glossary | '''gynecomastia''']], aspermatogenesis without a-Leydigism, and increased excretion of follicle-stimulating hormone.''' American Journal of Clinical Dermatology 1942; 2: 615–627.</ref>, is caused by the addition of one or more X chromosome(s) in affected males . He depicted a disorder characterised by [[#Glossary | '''gynecomastia''']] and a very specific type of [[#Glossary | '''hypogonadism''']], as well as an absence of [[#Glossary | '''spermatogenesis''']].

It is still largely associated with these defects, the most common including reduced fertility and [[#Glossary | '''hypogonadism''']]. A high proportion of affected men may remain asymptomatic their whole lives, this is because the severity of the disorder differs greatly from person to person<ref name="PMID21397196"/>.

The extra chromosome present is largely due to a genetic abnormality known as [[#Glossary | '''non-disjunction''']] that can occur during either mitosis or [[#Glossary | '''meiosis''']], this is described in detail below. It has also been suggested to be the most common disorder associated with [[#Glossary | '''non-disjunction''']] <ref name="PMID21397196"/>.

There are a number of diagnostic techniques currently used to determine accurate and early identification of the syndrome. This is particularly useful to encourage the implementation of the best treatment plan to manage the symptoms of the syndrome<ref><pubmed>20392711</pubmed></ref>. The phenotype of the syndrome differs significantly through the different stages of life, and a particular stage will correspond to the best management protocol for that point.

==History==

[[File:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities.png|thumb|right|250px|Figure 2:Steps in a classic array CGH-analysis used for the most common chromosomal abnormalities]]

Klinefelter syndrome (KS) was first described by Harry F. Klinefelter and his colleagues in 1942. Their observations of nine patients where characterised by a number of peculiar symptoms; [[#Glossary | '''gynecomastia''']], [[#Glossary |'''azoospermia''']], hyalinised and small testes, absent [[#Glossary|'''spermatogenesis''']], elevated levels of follicle-stimulating hormone (FSH) and [[#Glossary| '''hypogonadism''']]. <ref name="PMID17415352"><pubmed>17415352</pubmed></ref> <ref name="PMID21397196"/>
In 1956, an investigation was carried out with 7 patients with Klinefelter’s syndrome that had the buccal smears that demonstrated Barr bodies . However, the cause of the syndrome remained unknown until 1959, when Jacobs and Strong discovered that a patient with KS had 47 chromosomes, including an extra X chromosome in the karotype of the patient <ref name="PMID17415352"/>. As recorded in their article 'A case of human intersexuality having a possible XXY sex-determining mechanism';

{| align="center"| style="border"
|- align="center" | bgcolor = "DDCEF2"
|''“…There are strong grounds, both observational and genetic, for believing that human beings with chromatin-positive nuclei are genetic females having two X chromosomes. The fact that this patient is chromatin-positive and has an additional chromosome within the same size range as the X, as well as an apparently normal Y, makes it seem likely that he has the genetic constitution XXY”''<ref name="PMID13632697"><pubmed>13632697</pubmed></ref>
|}

This discovery confirmed that the Barr bodies seen in patients with KS corresponds to an extra X chromosome<ref name="PMID13632697"/>. In 1966, Harry F. Klinefelter reported that the extra X chromosome results from either meiotic nondisjunction or anaphase lag. Anaphase lag describes a chromosome which is not incorporated into the new cell in the second stage of mitosis(anaphase) due to it ‘lagging’, resulting in gametes lacking a sex chromosome <ref name="PMID3529433"><pubmed>3529433</pubmed></ref>.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, [[#Glossary | '''androgen''']] deficiency and reduced intelligence<ref name="PMID17415352"/>. However, a few years after the syndrome was described Heller and Nelson reported that the gynacomastia was not a necessary part of the syndrome, even though it occurred in about 75% of the patients which they observed. The hallmarks of the syndrome were then thought small testes, sterility and increased excretion of follicle stimulating hormone<ref name="PMID3529433"/>. Extensive studies of these patients during their adolescence illustrated the various personality traits, which can be handled by proper counselling. Similar to today, Harry Klinefelter reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding.

Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.

===Timeline===

{| style="border: solid 1px #a0a0ff"
|- align="center"
|-bgcolor="DDCEF2"
|style="width:50px"|'''Year'''
| '''Discovery'''
|-
| valign="top" bgcolor="DDCEF2"|'''1942'''
| valign="top" bgcolor="lightyellow" | Dr. Harry Klinefelter and his co-workers at Massachusetts General Hospital in Boston published a report on 9 men describing the signs and symptoms of Klinefelter’s Syndrome. The ‘prototypic’ man with Klinefelter’s syndrome was described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. <ref name= "PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1949'''
| valign="top" bgcolor="lightyellow" | Barr and Bertram noticed positive [[#Glossary | '''chromatin''']] material in KS patients.It was a dense chromatin mass which they later termed, Barr body.
|-

| valign="top" bgcolor="DDCEF2"|'''1956'''
| valign="top" bgcolor="lightyellow" | The discovery of [[#Glossary | '''Barr bodies''']] as a result of the new development of Buccal smears
|-

| valign="top" bgcolor="DDCEF2"|'''1959'''
| valign="top" bgcolor="lightyellow" | Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.
|-

| valign="top" bgcolor="DDCEF2"|'''1960s'''
| valign="top" bgcolor="lightyellow" | Development of chromosome banding techniques. <ref><pubmed>5640698</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1962'''
| valign="top" bgcolor="lightyellow" | Maclean and Mitchell’s studies on inmates in prisons and institutions for mental health revealed an increased risk of psychiatric disorders, mental retardations and criminal behaviour in patients with Klinefelter syndrome. <ref name="PMID17415352"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1966'''
| valign="top" bgcolor="lightyellow" |Dr. Harry Klinefelter reports that the extra X chromosome results from either meiotic [[#Glossary |'''non-disjunction''']] or anaphase lag. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1970'''
| valign="top" bgcolor="lightyellow" | Rozen et al reported that approximately 1% of all individuals institutionalised with mental retardation have an XXY karotype. <ref><pubmed>4398603</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1970s'''
| valign="top" bgcolor="lightyellow"| A number of centres began screening newborns for sex [[#Glossary | '''chromatin''']] abnormalities.
|-

| valign="top" bgcolor="DDCEF2"|'''1986'''
| valign="top" bgcolor="lightyellow"| Dr. Harry Klinefelter described that the hallmarks of the syndrome are now small testes, sterility and increased excretion of follicle stimulating hormone. <ref name="PMID3529433"/>

He also reported that most patients with this condition were not diagnosed until early adult life, when counselling may be less rewarding. <ref name="PMID3529433"/>

Treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients. <ref name="PMID3529433"/>
|-

| valign="top" bgcolor="DDCEF2"|'''1992'''
| valign="top" bgcolor="lightyellow"| The Comparative Genomic Hybridization (CGH) analysis was developed as a genome wide screening strategy for detecting DNA copy number imbalances.<ref><pubmed> 1359641</pubmed></ref> A classic array-CGH experiment is shown figure 2.
|-

| valign="top" bgcolor="DDCEF2"|'''1995'''
| valign="top" bgcolor="lightyellow"| Reiss et al., found that half all mental retardation in males originates from a defective gene on the X chromosome. Thus, the X chromosome comprises the genes involved in human cognition. <ref><pubmed>7585014</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''1998'''
| valign="top" bgcolor="lightyellow"| Smyth and Bremmer concluded that XXY karotypes occurs in 1 in 500 live male births and is the most common type of human chromosome anomaly. <ref><pubmed>9645824</pubmed></ref>

They also hypothesised that the characteristics features of Klinefelter’s syndrome originate from genes escape inactivation and are expressed in excess.
|-

| valign="top" bgcolor="DDCEF2"|'''2002'''
| valign="top" bgcolor="lightyellow"| Crow et al., suggested that at least one gene or genes in the X-Y homologous regions of the sex chromosomes which escape’s normal X- inactivation are crucial for language functioning.<ref><pubmed> 15729733</pubmed></ref>
|-

| valign="top" bgcolor="DDCEF2"|'''2010'''
| valign="top" bgcolor="lightyellow"| Stefano Gambardella et al., designed a targeted array called GOLD (gain or loss detection) Chip which detects unexpected major chromosome imbalances. <ref>Stefano G., Erika C., Francesca M., Giusy S., Francesca G., Michela B., Anna M. N., Antonio N., Ercole B., Laura B. and Giuseppe N.(2010) Design, Construction and Validation of Targeted BAC Array-Based CGH Test for Detecting the Most Commons Chromosomal Abnormalities. ‘’Genomic Insights.’’ 3:9-21</ref>
|-
|}

==Epidemiology==

[[File:Processing of social cues in both normal men and men with Klinefelter's Syndrome.jpg|thumb|right|Figure 2. The emotional response and comprehension of men with Klinefelter’s Syndrome differs from that of normal men]]

One of the most common disorders of sex chromosomes in humans is Klinefelter’s syndrome, otherwise known as 47,XXY gene mutations. This is prevalent in around 1 in 500 males<ref name="PMID17062147"><pubmed>17062147</pubmed></ref>. There can also be variations of this genetic condition, and these variations are referred to as chromosomal aneuploidies.
The chromosomal variations are present within 1 in 50 000 male births, so are much rarer than 47,XXY mutations. It is said that males born with Klinefelter’s syndrome often go through life without being [[#Glossary | '''karyotyped''']], meaning that they are left undiagnosed<ref><pubmed>9160389</pubmed></ref>. In around 80% of cases, the [[#Glossary | '''karyotype''']] for Klinefelter’s syndrome is shown in every cell of the body. The age of the mother and father at the time of conceiving a child has no relation at all to whether a child will be born with the condition.

[[File:Age and intellectual functioning of boys with Klinefelter Syndrome and normal males.png|thumb|left|Figure 3. The average intellect of boys with Klinefelter's Syndrome differs from that of normal males]]

A link was found between increased risk of mortality and Klinefelter syndrome. There was “a significant increase in mortality risk of 40% (hazard ratio, 1.40; 95% confidence interval, 1.13–1.74), corresponding to a significantly reduced median survival of 2.1 yrs.’’ <ref name="PMID15292313"><pubmed>15292313</pubmed></ref >The increased mortality was because of infections, neurological, circulatory, pulmonary, and urinary tract diseases which people with Klinefelter’s are more susceptible too. There are studies currently being conducted into whether socioeconomic background increases the risk of a child developing Klinefelter’s Syndrome<ref name="PMID15292313"><pubmed>15292313</pubmed></ref>.

Seizures can typically occur, and when seizures occur in males with Klinefelter's syndrome, it usually happens between 3 months and 3 years of age. Neuro-imaging tests have failed to identify the cause of the seizures<ref name="PMID20438626"><pubmed>20438626</pubmed></ref>. It is very difficult to diagnose a child with Klinefelter's syndrome immediately, since many of the symptoms that are exhibited in childhood may be due to other factors, such as shyness, stress, and social phobia. Across are two graphs adapted from recent studies which demonstrate both the emotional response to stimuli of men with Klinefelter's syndrome, and the intelligence of males with Klinefelter's syndrome compared to normal males.

It has also been suggested that men with Klinefelter's syndrome are 50% more at risk of being diagnosed with breast cancer <ref><pubmed>20463819</pubmed></ref>

==Aetiology==

Chromosome abnormalities have a high incidence in humans. The most common type is [[#Glossary | '''aneuploidy''']], which is the loss (monosomy) or gain (trisomy) of an entire chromosome <ref name="PMID12926525"><pubmed>12926525</pubmed></ref>. [[#Glossary | '''Aneuploidy''']]’s occur in approximately 5% of pregnancies which survive long enough to be seen and approximately 10-25% of all fertilised human oocytes are either monosomic or trisomic <ref name="PMID12926525"/>. Trisomies are incapable of normal development, the consequences are less severe for the sex chromosomes than the autosomes, leading to enhanced sex chromosomes among live-borns in comparison with autosomal trisomies. Therefore, the 47,XXY condition, termed Klinefelter’s Syndrome (KS) is identified in almost 1 of every 1000 male births, causing it to be one of the most commonly identified chromosome abnormality among live-born individuals.

===Non-Disjunction===

[[#Glossary | '''Non-disjunction''']] is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by [[#Glossary | '''non-disjunction''']] during the first and second meiotic divisions, however, XXY of paternal origin can only occur during the first meiotic division. In the great majority of trisomies the additional chromosome is of maternal origin and results from an error during the first meiotic division as seen in figure 1. However, the 47,XXY has been extensively studied and around one half of all cases are paternally derived. The nature of the errors by which maternal and paternal XXYs can arise are extremely diverse. The process of [[#Glossary | '''meiosis''']] serves to generate haploid gametes through a specialised cell division process, consisting of two stages of cell division, MI and MII. During prophase of MI the pairs of homologous chromosomes synapse and undergo recombination, with chiasmata being formed at the sites of exchange. Their purpose is to link together the homologues and therefore play a crucial role in the proper disjunction of chromosomes in the first meiotic division<ref name="PMID12926525"/>.

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20I.htm Animation Meiotic Non-disjunction - Meiosis I]

[http://www.biostudio.com/d_%20Meiotic%20Nondisjunction%20Meiosis%20II.htm Animation Meiotic Non-disjunction - Meiosis II]

<gallery>
File:Meiotic non-disjunction.jpg | Meiotic Non-disjunction in Comparison with Normal Disjunction

File:Nondisjunction of Homologous Chromosomes in Meiosis1.jpg | Figure 5. Nondisjunction of Homologous Chromosomes in Meiosis 1

File:Nondisjunction of Sister Chromatids in Meiosis 2.jpg | Figure 6. Nondisjunction of Homologous Chromosomes in Meiosis 2

File:Maternal Non-Disjunction.PNG | Figure 4. Maternal Non-disjunction
</gallery>

===Genetics===

Although many other genes are important for proper sexual development of the male foetus, the SRY (sex-determining region of Y chromosome) gene located on the Y chromosome directs the development of the foetal gonads into testes. Typically, when two or more X chromosomes are present in a cell, as in healthy females or sex chromosome disorders like 47,XXY, only one is active. The additional X chromosome is mostly inactive and the X [[#Glossary | '''chromatin''']] is perceived as a Barr body in the periphery of the cell nucleus<ref name=PMID"21521364"<pubmed>21521364</pubmed></ref>.
In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR) <ref><pubmed> 20228051</pubmed></ref> which remain active in men and woman <ref name="PMID21521364"/>. They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during [[#Glossary | '''meiosis''']] in males. Some genes in the X chromosome which are not homologous to the Y chromosome can escape inactivation and are functionally duplicated in KS males<ref name="PMID21521364"><pubmed>21521364</pubmed></ref>.

==Pathogenesis==

Abnormal chromosome distribution, which leads to Klinefelter’s syndrome, is the result of one of two mechanisms. These are anaphase lagging and [[#Glossary | '''non-disjunction''']]. The latter of the two, [[#Glossary | '''non-disjunction''']], takes place more often.<ref>Cynthia M. Smyth, William J. B. '''Klinefelter Syndrome''' Arch Intern Med. 1998;158:1309-1314</ref>

===Anaphase Lagging===

In the anaphase phase of cell division, spindle fibers attach to sister chromatids and separate them. However, in the abnormal event of anaphase lagging, some spindle fibers are missing. Because of this, sister chromatid will not be successfully separated but together will be incorporated into a single daughter nucleus. As a result, the daughter cell will have a supernumerary chromosome.

===Non-disjunction===

This more common aberrant cell division takes place during [[#Glossary | '''gametogenesis''']]. More specifically, it is the event of the homologous chromosome or sister chromatid failing to separate normally. So like anaphase lagging, the distribution of genetic content in the daughter cells is uneven. [[#Glossary | '''Non-disjunction''']] can take place in the first or the second meiotic division. In addition, it can also occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with a greater number of X chromosomes. Some examples of these variants are 48,XXXY and 48,XXXXY. Furthermore, [[#Glossary | '''non-disjunction''']] can also take place in postzygotic division. <ref>Bandmann, H. J., Breit, R., & Perwein, E., (1984). '''Genetics and Cytogenetics of Klinefelter's Syndrome: [[#Glossary | '''Karyotype''']] of Klinefelter's Syndrome and Its Variants.''' In H. J. Bandmann, B. Reinhardt, & E. Perwein, Klinefelter's Syndrome (1, pp. 1-229). New York, America: Springer-Verlag.</ref>

As depicted in Figure 5, when [[#Glossary | '''non-disjunction''']] takes place in the first meiotic division, a homologous pair of chromosomes is not separated in the anaphase 1. The result is one daughter cell having three chromosomes while the other has only one by the end of [[#Glossary | '''meiosis''']] -1. The daughter cell with one chromosome is not viable. When the daughter cell with three chromosomes is followed through [[#Glossary | '''meiosis''']] two, its own progeny can be seen to include either a parental and maternal X chromosome or two copies of the maternal X chromosome.

However, if [[#Glossary | '''non-disjunction''']] occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase 2. This is seen in Figure 6. By the end of the second [[#Glossary | '''meiosis''']] one daughter cell contains both sister chromatids of the maternal X chromosome, while the other daughter cell does not contain that maternal genetic material.

The consequence of [[#Glossary | '''non-disjunction''']] is that an XX ovum or a XY sperm will be produced. This gamete will then go on to be fertilised by a normal Y sperm or an X ovum respectively and conclusively produce a XXY zygote, which is the hallmark of Klinefelter’s syndrome.

==Signs and Symptoms==

Symptoms may differ slightly depending on the stage of development. Screening is recommended when a combination of the following signs of Klinefelter’s syndrome are observed.

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Age
| Signs and Symptoms
| Image
|-
| '''Birth'''
|
*Cryptorchidism (1 or 2 testes have not dropped into the scrotum from the abdominal cavity)
*Small penis
*Hypotonia (reduced muscle tone)
*Scrotum Bifidus
*Inguinal Hernia
*Cleft Palate<ref>http://www.genome.gov/19519068</ref>
| [[File: Comparing age and intellect of a Klinefelter group a non-clinical control group.PNG|thumb|center|Comparing age and intellect of a Klinefelter group and a non-clinical control group]]
|-bgcolor="FAF5FF"
| '''Infancy'''
|
*Learning difficulties (severity is proportional to number of extra X chromosomes)
*Delayed speech and language deficits
*Motor delay or dysfunction
*Attention deficits
*Small penis and testes
*Long limbs<ref>http://emedicine.medscape.com/article/945649-clinical#a0217</ref>
|-
| '''Childhood'''
|
*Small, firm testicles
*Verbal cognitive deficits
*Speech difficulties
*Trouble with spelling, reading and mathematics
*Mood and Behavioral problems
*Difficulty expressing feelings and socializing<ref>Schlatt S, Hillier SG &Foresta C, ''' Klinefelter’s syndrome: from chromosome to clinic''' Molecular Human Reproduction 2010;16: 373– 374</ref>
|-bgcolor="FAF5FF"
| '''Puberty'''
|
* [[#Glossary | '''gynecomastia''']] (enlarged breasts)
*Long limbs but short trunk
*Above average, accelerated height
*Reduced muscle bulk
*Scarce facial and body hair
*Delayed or incomplete pubertal development
*Low energy levels
| [[File: Pubertal gynecomastia.jpg|thumb|center|Pubertal gynecomastia]]
|-bgcolor="FAF5FF"
| '''Adulthood'''
|
*Other mental difficulties (eg. unable to make plans or solve problems)
*Osteoporosis (due to decreased bone mineral density) <ref>Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. '''Klinefelter Syndrome''' Am Fam Physician. 2005 Dec 1;72(11):2259-2262.</ref>
*Low testosterone levels
*Infertility due to a lack of sperm
*Under average testicular volume
*Problem with penile erection
* Decreased Libido (sexual desire)
|-bgcolor="FAF5FF"
|}

==Diagnosis==

===Karyotype===

Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the [[#Glossary | '''karyotype''']] analysis will show 46,XY. But in a Klinefelter's syndrome patient, the [[#Glossary | '''karyotype''']] is often observed to be 47,XXY. The featured image is an example of a typical [[#Glossary | '''karyotype''']] of a Klinefelter's syndrome patient.

[http://www.youtube.com/watch?v=F7trv8c3Vlo Movie on the process of karyotyping]

===Statistics===

The chances of diagnosing KS are, unfortunately, very low. In one study, only 36% of KS patients are diagnosed, of which 10% of the KS patients being diagnosed prenatally and 26% post natally. This shows that diagnosis methods are not easily accessed and performed.
<ref>Abramsky L, Chapple J. '''47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling.''' Prenat Diagn 1997;17:363 – 368</ref>

===Prenatal Diagnosis methods===

Prenatal diagnosis is most common achieved by two methods, either by amniocentesis or chorionic villus sampling (CVS). As both are invasive procedures, they have considerable risks. Most often these diagnosis methods are performed because other genetic defects are suspected, such as Down ’s syndrome, because of an advanced maternal age. Therefore, the diagnosis of KS is often considered a chance finding.

Amniocentesis can be done from approximately 14 weeks gestation, it involves the sampling of amniotic fluid. The amniotic fluid contains fetal DNA and cells, proving very useful for such
testing.
[[File:Karyotype of a Klinefelter's syndrome patient.jpg|left|300px|Karyotype of Klinefelter's Syndrome|thumb]]A needle is passed into the mother’s abdomen and into the amniotic cavity. This process is always used in conjunction with an ultrasound, to ensure the best conditions are available, ie fetal position in womb. <ref><pubmed>15758614</pubmed></ref>

For CVS, a catheter is passed through the mother’s vagina and into the uterus using ultrasound imaging. From here, cells from the chorionic placenta can be sampled for future testing. This can be carried out in the first trimester of pregnancy, a significant benefit over amniocentesis. However, there is a risk of miscarriage with this test, especially when compared to the process amniocentesis. <ref><pubmed>21413037</pubmed></ref>

The cells from both samples are then cultured until there are sufficient numbers of cells. An enzyme is then added that halts proliferation at a point when the chromosomes are condensed. These chromosomes are then stained and, using a light microscope, any abnormalities can be identified. <ref><pubmed>135003</pubmed></ref>

===Diagnosis at birth===

Although this rarely takes place, some clinical features may make physicians suspect and ask for a [[#Glossary | '''karyotype''']] analysis.
Some abnormalities include:

• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)

• ﬁfth ﬁnger clinodactyly

• cleft palate

• inguinal hernia <ref>Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. '''Genital anomalies in Klinefelter’s Syndrome.''' Horm Res 2007;68:150 – 155.</ref>

===Postnatal Diagnosis Methods===

[[File:Fluorescence In situ Hybridization (FISH) assay.JPG|Figure. 8|FISH showing the number of X chromosomes within a nuclei|thumb|right|300px]]

Postnatal diagnositic test for Klinefelter’s syndrome are often performed because physicians may suspect it because of clinical findings. As described in the ‘Signs and Symptoms’ section, some clinical findings may include patients suffering from infertility, learning disabilities and osteoporosis. Furthermore, a blood test of a Klinefelter’s syndrome patient may show high levels of follicle stimulating hormone, luteinizing hormone and low levels of testosterone. <ref>http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3</ref>

Postnatal karyotyping is a process where a blood sample is analysed. [[#Glossary | '''Leukocytes''']] from the patient’s blood sample are separated and then cultured. They are halted in the cell cycle when the chromosomes are condensed and can be stained. A photograph is taken of the chromosomes from one cell. Then they are organized according to size, number and structure and then observed for abnormalities.<ref><pubmed>15183749</pubmed></ref><ref>http://www.genome.gov/19519068</ref>

==Management==

===Androgen Therapy===

[[#Glossary | '''Androgen''']] therapy involves the replacement of testosterone. This is primarily given to stimulate the onset of puberty in affected males. Ideally, testosterone is given from the age that puberty usually occurs, in order to encourage normal development. In addition to this, it assists in treating or preventing some of the more typical clinical presentations of this disorder. Testosterone replacement encourages secondary sexual attributes, and helps ensure standard bone and muscle mass<ref><pubmed>20482304</pubmed></ref>.

Samango-Sprouse ''et al'' found that the initiation of [[#Glossary | '''androgen''']] therapy early in life was highly associated with improvments in speech and cognition, and other neurogical development. This research was based around children with severe Klinefelter's syndrome - 49,XXXXY. This gives much hope to the prospect of early treatment resulting in normal development of those afflicted with Klinefelter's syndrome. <ref><pubmed>21362043</pubmed></ref>

[[File:Action of Amoratase Inhibitors on Production of Estradiol.JPG|right|thumb|Action of Inhibitors on the Conversion of Testosterone to Estradiol]]

However, it has also been associated with a decrease in fertility, especially if given early in life. Premature treatment has been suggested to result in delayed puberty and abnormal physical development during this period<ref name="PMID18832949"/>. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment<ref name="PMID18832949"><pubmed>18832949</pubmed></ref>. <ref><pubmed>21655260</pubmed></ref>

===Fertility===

Aromatase inhibitors can be administered to men, in order to lower intratesticular estradiol levels. This is thought to encourage the production of testosterone and activate [[#Glossary | '''spermatogenesis''']]<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>. There are two main methods used to treat non-obstructive [[#Glossary | '''azoospermia''']], microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in [[#Glossary | ''' ''in vitro'' fertilisation''']] (IVF).
It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage<ref><pubmed>21811543</pubmed></ref>, and so conventional TESE is slowly being replaced by microdissection TESE. The most common IVF technique used in these situations is intracytoplasmic sperm injection, where a single sperm is injected into a single oocyte. This means that for the highest chance of success, the extraction of both the sperm and the egg need to be well timed<ref><pubmed>21716935</pubmed></ref>.
Before surgery, men are usually administered aromatase inhibitors for a few months. This is to restore the ratio of testoserone to esradiol back to normal levels, and to encourage the amount of viable sperm present<ref name="PMID11792932"><pubmed>11792932</pubmed></ref>.

==Other Similar Defects==

{| width="90%" cellspacing="1" cellpadding="1"
|-bgcolor="DDCEF2"
| Abnormality
| Description
| Similarities
| Differences
| Image
|-
| '''Turner Syndrome (XO)'''
| This is a condition where a female only has one sex chromosome (45,XO). Girls with Turner syndrome lack certain characteristics, such as full grown ovaries, metabolic problems, short stature and decreased life expectancy <ref><pubmed>21454226</pubmed></ref>.
In embryology, the embryo may present with a web-like neck, low birth length and lymphedema of the dorsum of hands and feet. There may also be a delay in puberty because of gonadal [[#Glossary | '''dysgenesis''']]. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system <ref><pubmed>21271130</pubmed></ref>.
|
*Abnormal [[#Glossary | '''karyotype''']]
*People are also generally infertile
*The phenotype of is very variable, in that girls may present with the standard symptoms from it as aforementioned, or they may be asymptomatic and blend in with the rest of the population
*People with Klinefelter’s and Turners may both have learning difficulties, and difficulties with social interaction <ref><pubmed>21818630</pubmed></ref>
|
*Results from the loss of a chromosome, as opposed to the addition of a chromosome
*Many females with Turner’s syndrome have normal intelligence, whereas males with Klinefelter’s syndrome tend to have slightly below average intelligence
| [[File:Immunoglobulin levels in 15 girls with Turner Syndrome.png|thumb|center|Immunoglobulin levels in 15 Turner girls. The shaded boxes indicate the 95% confidence interval for the 5–20 years age group. Girls with recurrent otitis media are illustrated with open symbols (n = 8) and those who are otitis free with filled symbols (n = 7)]]
|-bgcolor="FAF5FF"
| '''47,XYY'''
| This is a condition where a male inherits an extra Y chromosome. The additional Y chromosome is from the father (paternal origin) and there is existing evidence that spermatocytes with additional Y chromosomes are selected against during [[#Glossary | '''gametogenesis''']] <ref><pubmed>10545600</pubmed></ref>. This condition only affects males.
This condition is not usually passed on from parents to offspring, and it has been shown that the sperm of 47,XYY males has the normal [[#Glossary | '''karyotype''']] <ref><pubmed>18037669</pubmed></ref>.
|
*Results from the addition of a chromosome
*Boys have an increased risk of having learning difficulties which could begin in their early childhood
*Boys with 47,XYY may have a slightly lower IQ than their peers
|
*The condition is completely asymptomatic in most cases, this is the reason for the debate regarding whether it should be termed a ‘syndrome’
*Boys with 47,XYY Syndrome are fertile and produce normal testosterone levels
*Boys with 47,XYY syndrome tend to have some impairment in language development, albeit minor, whereas boys with Klinefelter’s syndrome have some form of motor impairment function <ref><pubmed>20014371</pubmed></ref>
| [[File:Karyogram of male with 47, XYY Syndrome.png|thumb|center|Karyogram of male with 47,XYY Syndrome]]
|-
| '''48,XXYY'''
| 48,XXYY, frequently referred to as another variant of Klinefelter’s syndrome, is an anomaly whereby males have an extra X and Y chromosome. Sometimes, renal clearance can be affected by this condition. This is caused by low levels of serum urate in conjunction with high levels of renal urate clearance <ref><pubmed>3714610</pubmed></ref>.
|
*The physical phenotype of the condition is very similar to Klinefelter’s Syndrome, since males have a tall stature, have learning disabilities and are infertile <ref><pubmed>18481271</pubmed></ref>
|
* In some cases, signs of [[#Glossary | '''acromegaly''']] have been seen in some patients with this variant, as demonstrated in a study of a 24 year old male living in Japan <ref><pubmed>8389624</pubmed></ref>
| [[File:Male with 48,XXYY Syndrome.png|thumb|center|Male with 48,XXYY Syndrome]]
|-bgcolor="FAF5FF"
|}

==Current Research==

'''Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI; 2011'''

It is suggested that the addition of an X chromosome has a significant impact on neural systems. The X chromosome contains a large number of genes responsible for neural system development, and so Klinefelter's syndrome was the ideal model for the observation of neural development abnormalities. van Rijn ''et al'' used fMRI (functional magnetic resonance imaging) to observe the activity in specfic parts of the brain. People with Klinefelter's syndrome are generally socially disadvantaged, and so a link was investigated between neural activity and social cues.

It was found that Klinefelter's syndrome can be associated with decreased activity in specific neural systems. This also advocates the possibility of using Klinefelter's syndrome as a model for further study of the X chromosome. <ref><pubmed>21737434</pubmed></ref>

'''Insights into the pathogenesis of XXY phenotype from comparison of the clinical syndrome with an experimental XXY mouse model; 2010'''

Even after all we now know about Klinefelter's syndrome, a lot still remains a mystery. This is particularly due to the absence of a commonly used animal model. Lue ''et al'' investigated the ultimate similarities of a mouse 41,XXY model (as opposed to the human 47,XXY), and it's use in further research. It is important to have an animal model that largely resembles the human syndrome or disease. Lue ''et al'' used this model to compare phenotypic similaries between the two, in regards to hormonal imbalances and effect of additional X chromosome genes.

By the comparison of the animal model and human representative, they found that clinical symptoms and phenotype typical in Klinefelter's syndrome are likely due to an avoidance of the inactivation of the X chromosome. <ref><pubmed>21217605</pubmed></ref>

'''Expression of selected genes escaping from X inactivation in the 41, XXY* mouse model for Klinefelter’s syndrome; 2010'''

It still remains a debate as to the exact molecular and genetic actions that result in the presentation of Klinefelter's syndrome. It has been suggested that some of the genes on the X chromosome escape inactivation and so result in the clinical symptoms of Klinefelter's syndrome. Werler ''et al'' explored this theory using two mouse models (41,XXY and 41,XXY*) and epigenetics. Out of the genes that were obseved in this study, they all seemed to undergo escape from X chromosome inactivation similarly to female mice.

There were also noticable tissue differences, wherein gene expression in the brain was significantly different to that of the liver and kidney. In the brain there was substantial upregulation of these "X-linked excapee genes". This is suggested to directly affect the phenotypic presentation of 47,XXY syndrome. <ref><pubmed>21241365</pubmed></ref>

==Glossary==

* '''Acromegaly''' - This is a condition caused by abnormal hormone production from the pituitary gland, resulting in altered growth of hands, feet, and face

* '''Androgen''' - A male sex hormone, ie testosterone

* '''Aneuploidy''' - Abnormal number of chromosomes

* '''Azoospermia''' - Occurs when males have little to no motile sperm in the semen

*'''Barr bodies''' - Inactivated X chromosome in females due to sex being determined by W or Y chromosomes instead of XY

*'''Buccal mucosal cells''' - Cells of the oral cavity that secrete mucus

*'''Chromatin''' - The genetic material that forms chromosomes, it is also composed of DNA

*'''Dysgenesis''' - Defective or abnormal development of an organ, especially of the gonads

*'''Gametogenesis''' - Biological process by which haploid or diploid cells undergo division and/or differentiation to form mature haploid gametes.

*'''Gonadotropin''' - Protein hormones secreted by gonadotrope cells of the pituitary gland.

*'''Gynecomastia''' - Is the abnormal development of large mammary glands in males which give large breasts.

*'''Hyalinised''' - The state of something being hyaline (clear and translucent)

*'''Hypogonadism''' - Occurs when the sex glands produce little to no hormones.

*'''In vitro fertilisation''' - The process of fertilising an oocyte by sperm outside the womb.

*'''Karyotype''' - Number and/or appearances of chromosomes in a eukaryotic cell nucleus

*'''Leukocytes''' - White blood cells which are cells of the immune system

*'''Meiosis''' - The process of cell division of germ (sex) cells resulting in 4 daughter cells.

*'''Mosaicism''' - The presence of two or more genetically different cells in one organism

*'''Non-disjunction''' - The failure of chromosomes to separate properly during cell division. This results in abnormal chromosome number in daughter cells.

*'''Pituitary gland''' - Endocrine gland that secretes hormones that regulate homeostasis.

*'''Post zygotic non-disjunction''' - This occurs when chromosomes do not separate during mitosis, and the cells are not removed by the usual 'proof-reading' mechanisms.

*'''Seminiferous tubule''' - Long, thread like tubes found in the testes and are the specific location of meiosis in the body.

*'''Sertoli cells''' - Cell of the testes that is part of the seminiferous tubule. It is activated by Follicle Stimulating Hormone

*'''Spermatogenesis''' - Process by which male germ cells undergo division and produce a number of cells referred to as spermatogonia, through which spermatocytes are derived from.

==References==

--[[User:S8600021|Mark Hill]] 00:25, 15 September 2011 (EST) You need to fix your referencing so that multiple entries for the same reference are not listed here (see ref 18 which I have amended in the text).

<references/>
----

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Table 1. Age and intellectual functioning (mean, SD) in the Klinefelter group as compared to the non-clinical control group.<ref>Ranjith Ramasamy, Joseph A Ricci, Gianpiero D Palermo, Lucinda Veeck Gosden, Zev Rosenwaks, Peter N Schlegel '''Successful fertility treatment for Klinefelter's syndrome.''' J. Urol.: 2009, 182(3);1108-13</ref>

===References===
<pubmed>19616796</pubmed>| [http://www.ncbi.nlm.nih.gov.wwwproxy0.library.unsw.edu.au/pubmed/196167962 PMID19616796]

Copyright - van Rijn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Figure 1 G-banded karyotype showing 47,XXY chromosomal complement (Klinefelter syndrome)

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

==References==
<pubmed>21716934</pubmed>| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114572 PMC3114572]

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