2011 Group Project 3
|Note - This page is an undergraduate science embryology student group project 2011.|
--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 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?
In normal meiosis (the process of the production of germ or sex cells) the resulting daughter cells will have only one sex chromosome, X or Y. Then, upon fertilisation, the genetic components of the two germ cells combine to form a single complete genome. This is complete with two sex chromosomes (out of 46), 46,XX for a female or 46,XY for a male. However, there a number of known abnormalities involved with the arrangement and functioning of these chromosomes. 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. .
In some very rare cases two or more extra copies of the X chromosome may be present (48,XXXY, or 49,XXXXY). This generally results in more emphasised clinical features typically present in Klinefelter's syndrome. In approximately 20% of cases, 46,XY/47,XXY mosaicism can occur.  This refers to the situation where the extra chromosome is only present in some cells, mostly due to errors occurring during mitosis.
Klinefelter's syndrome usually presents with a few standard clinical abnormalities. Affected men generally have reduced fertility and suffer from hypogonadism. However, a high proportion of affected men may not show any symptoms and the severity of the disorder differs greatly from person to person. It is suggested to be one of the most common conditions caused by non-disjunction. Diagnosis is usually done by karyotyping, which allows a look at all of the chromosomes and thus identification of a chromosomal disorder. This can also be done while the fetus is in the womb. This is a huge step forward, in the past most cases were identified significantly later in life by the clinical symptoms. Early diagnosis means the implementation of treatment earlier and thus the increased potential for normal development. 
This disorder was first described by Harry F. Klinefelter in 1942 . He described a disorder characterised by gynecomastia and a very specific type of hypogonadism, as well as an absence of spermatogenesis.
Klinefelter's syndrome is mainly managed by testosterone replacement therapy. This encourages normal development through puberty, and helps counteract some of the typical clinical symptoms of the syndrome.  There are also fertility treatments available that have shown mdoerate success, giving men with Klinefelter's syndrome the opportunity to reproduce. 
There has been significant recent research in understanding the neural developmental implications of having an extra X chromosome.  Klinefelter's syndrome has even been used as a model to further understand development and the role the X chromosome plays. With the increased use of animal models, much has been revealed about the syndrome that was not previously known. 
Klinefelter syndrome 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.  
In 1949, Murray L. Barr and Ewart G. Bertram discovered that patients with Klinefelter’s syndrome had positive sex chromatin material in their epithelial cells, this is normal for females but not in males.  It was a dense chromatin mass which they later termed, Barr body. This discovery led to the use of smears of stained buccal mucosal cells which determined whether the infant’s genetic sex matched the phenotypic sex.
The late 1950’s led to a breakthrough in understanding Klinefelter’s syndrome. In 1956, investigations described 7 patients with Klinefelter’s syndrome as a result of 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. This discovery confirmed that the Barr body seen in patients with KS corresponds to an extra X chromosome. Harry F. Klinefelter in 1966, 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. Subsequent studies have shown other aberrations of the X chromosome in KS, these include 48,XXXY and mosaicism.
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’s syndrome, these findings were reported by Maclean and Mitchell in 1962. Since the 1960’s, a number of studies have revealed more of Klinefelter syndrome, including the chromosome survey’s that identified unselected newborn babies with sex-chromosome aberrations. These individuals were followed up throughout the 1970s and 1980s, and focused on the development of affected individuals throughout infancy, childhood and adolescence.
The ‘prototypic’ man with KS was initially described as tall, with narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, androgen deficiency and reduced intelligence. 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. 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 is may be less rewarding. By the 1960s, there was no treatment for sterility and the treatment for gynecomastia was excision of the tissue with preservation of the nipple. They also treated hypogonadism with injected testosterone, and thought this also aided personality abnormalities in adolescent patients.
Below is a timeline highlighting all the major advancements and developments in Klinefelter’s Syndrome.
|1942||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.|
|1949||Barr and Bertram noticed positive chromatin material in KS patients.|
|1956||The discovery of Barr bodies as a result of the new development of Buccal smears|
|1959||Jacobs and Strong discovered that it was a chromosomal disorder, with the appearance of an extra X chromosome.|
|1966||Dr. Harry Klinefelter discerns that it is caused from non-disjunction or an anaphase lag.|
|1970s||A number of centres began screening newborns for sex chromatin abnormalities.|
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. 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 karyotyped, meaning that they are left undiagnosed. Males born with Klinefelter syndrome often fail to produce sperm, and have very low testosterone levels due to largely to them having small testes. They have increased susceptibility to diabetes, cardiovascular disease and cancer, although it is still unclear why.
In around 80% of cases, the 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. The appearance or phenotype of Klinefelter syndrome often becomes evident after puberty. Prior to puberty, the pituitary gland and gonad function is relatively normal in sufferers. Males with Klinefelter’s syndrome generally have IQs which are 10-15 points lower than the general population. Interestingly, these differences in IQ levels were only minor. There is also a decreased head circumference found in XXY males as opposed to normal karyotype males. As well, males with Klinefelter’s syndrome generally have delayed speech development. There is also a higher chance that those affected will experience behavioural problems, possibly due to lower IQ levels.
The vast majority of males are not diagnosed prenatally with Klinefelter’s syndrome. A typical male suffering from Klinefelter’s is characterized by abnormally long legs and arm span, feminine-like distribution of adipose tissue including a condition known as gynecomastia, absent or decreased facial and pubic hair as well as small hyalinized testes and a small penis . There has also been an association hypothesized between tooth size and Klinefelter's syndrome. This could be attributed to a growth gene which may be found in the Y chromosome, as opposed to the X chromosome since females have a smaller crown size than males. Since 47,XXY males have a taller body stature than normal males, it is not a surprise that Klinefelter sufferers have larger tooth sizes.
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. 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.
Chromosome abnormalities have a high incidence in humans. The most common type is aneuploidy, which is the loss (monosomy) or gain (trisomy) of an entire chromosome . 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 . 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 is the failure of chromosome pairs to separate during the first and second meiotic divisions. Maternal XXY can be caused by 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 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.
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 chromatin is perceived as a Barr body in the periphery of the cell nucleus.  In addition to specific regions, both sex chromosomes carry short regions of homology termed pseudoautosomal regions (PAR)  which remain active in men and woman . They behave as an autosome and function to allow X and Y chromosomes to pair and properly segregate during 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. 
There are two mechanisms by which chromosome distribution can be abnormal and lead to Klinefelter’s syndrome. These are anaphase lagging and nondisjunction. The latter of the two is the process which takes place more frequently, when compared to the first.
During anaphase in the cell division, spindle fibers attach to sister chromatids and separate them. However, the abnormal event of anaphase lagging involves spindle fibers missing. Because of this, sister chromatid will not be successfully separate but together will be incorporated into a single daughter nucleus. Thus resulting in a supernumerary chromosome present in a gamete or zygote.
The more common aberrant cell division, nondisjunction takes place during 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 amongst the daughter cell is uneven. Nondisjunction can take place in the first or the second meiotic division. In addition, it can occur in both of the meiotic division, leading to variants of Klinefelter’s syndrome with greater number of X chromosomes, such as 48,XXXY and 48,XXXXY. Furthermore, nondisjunction can also take place using postzygotic division. If nondisjunction takes place in the first meiotic division, this means that during the anaphase phase a homologous pair of chromosomes is not separated. The result is, at the end of the first meiosis, one daughter cell having three chromosomes while the other has only one. The daughter cell with one chromosome is not viable. When the daughter cell containing the remaining three chromosomes is followed through meiosis two, its own progeny will include a parental and maternal X chromosome or two copies of the maternal X chromosome.
However, if nondisjunction occurs in the second meiotic division, then the abnormal separation of genetic material takes place in anaphase two. As a result, by the end of the second 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 nondisjunction 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.
As a result of this genetic mutation, the characteristic shrunken testes and the absence of motile sperm of the Klinefelter syndrome can be observed. These symptoms indicate that the seminiferous tubule and sertoli cells have lost its function. This has many consequences, one of which is the decreased inhibin hormone level. This in turn results in the elevation of gonadotropin level, which is the hallmark of Klinefelter syndrome.
Gonadotropin levels increases as a result of low levels of inhibin because it act as a feedback inhibitor on the pituitary gland. However, the elevated gonadotropin level can only be observed during and after puberty. This is shown in a study with prepubertal boys. One group of subjects have an additional X chromosome while the control group did not. By comparing the two groups a difference in the gonadotropin level was not observed.
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.
Karyotyping is a process where the number of chromosomes and their structures are observed for any abnormalities. In a healthy male subject, the karyotype analysis will show 46,XY. But in a Klinefelter's syndrome patient, the karyotype is often observed to be 47,XXY. The featured image is an example of a typical karyotype of a Klinefelter's syndrome patient.
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. 
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. 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 foetal position in womb. 
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. 
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. 
Diagnosis at birth
Although this rarely takes place, some clinical features may make physicians suspect and ask for a karyotype analysis. Some abnormalities include:
• genital abnormalities (eg. cryptorchidism, small penis, scrotum biﬁdus and hypospadias)
• ﬁfth ﬁnger clinodactyly
• cleft palate
• inguinal hernia 
Postnatal Diagnosis methods
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. 
Postnatal karyotyping is a process where a blood sample is analysed. 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.
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.
Samango-Sprouse et al found that the initiation of 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. 
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. It is also recommended to stop testosterone replacement a few months prior to the administration of infertility treatment.
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 spermatogenesis. There are two main methods used to treat non-obstructive azoospermia, microdissection testicular sperm extraction (TESE) and conventional TESE. These are methods of extracting what sperm is present in the testes for use in in vitro fertilisation (IVF). It has been shown that microdissection TESE has a higher rate of extraction, and allows for minial testicular damage, 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. 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. 
Other Similar Defects
|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 .
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 dysgenesis. As well as all this, there may also be congenital defects of the heart, kidney and autoimmune system .
|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 gametogenesis . 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 karyotype .
|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 .||
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. 
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. 
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 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. 
--Mark Hill 07:50, 15 September 2011 (EST) Try bullet listing your glossary it looks neater and maybe remove the letter sub-headings it is too spread out on the project page, up to you.
- 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.
- X and Y chromosomes - X chromosomes come from the female and code for some female characteristics. Y chromosomes come from the male and code for male characteristics. XX is for a female and XY is for a male.
--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).
- 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.
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- Cynthia M. Smyth, MD; William J. Bremner, MD, PhD Klinefelter Syndrome. Arch Intern Med. 1998;158:1309-1314
- Schlatt S, Hillier SG &Foresta C, Klinefelter’s syndrome: from chromosome to clinic Molecular Human Reproduction 2010;16: 373– 374
- Daniel JW, MAJ, MC, USAF, and Maximilian M, M.D. Klinefelter Syndrome Am Fam Physician. 2005 Dec 1;72(11):2259-2262.
- 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
- Lee YS, Wai Fun Cheng A, Ahmed SF, Shaw JN, Hughes AI. Genital anomalies in Klinefelter’s Syndrome. Horm Res 2007;68:150 – 155.
- http://tidsskriftet.no/article/1695231 Week. 11 - 29 May 2008 Journal of Medical Unite 2008: 128:1281-3
2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip