Embryology - User contributions [en-gb]

User:Z3290841

2011-10-28T08:29:31Z

Z3290841:

-[[User:Z3290841|Z3290841]] 09:37, 30 July 2011 (EST)

==Lab 1 Assessment==
===Identify the origin of In Vitro Fertilization (IVF) and the 2010 nobel prize winner associated with this technique===
====Origin of IVF====
Studies and experiments about IVF have been going for more than a hundred years now. The first experiments and studies could date as far back as 1878, which involved the fertilisation of mammalian eggs in vitro, but were all unsuccessful. The source of this problem is the lack of knowledge about the need for egg cell maturation, sperm cell capacitation, and the correct media and condition for fertilisation. It was not until Austin and Chang coined and postulated sperm capacitaion that the technology produce more successful results.

====Robert Edwards====
He was the Nobel Prize laureate in 2010 in Physiology or Medicine for his contribution to the development of in vitro fertilisation. His work involved the development of a human culture media that allowed fertilisation and early embryo culture.
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===Identify a recent paper on fertilisation and describe its key findings===
Terada Y, Hasegawa H, Ugajin T, Murakami T, Yaegashi N, Okamura K.(2009).Microtubule organization during human parthenogenesis.''Fertility and Sterility'', 91(4), 1271-2. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/18706544

The key finding of the experiment that they did was the presence of multiple microtubule organising centre (MTOC) in human oocyte cytoplasm during parthenogenesis, which was previously only known to have been produced by the sperm centrosome in human fertilisation.
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===Identify 2 congenital anomalies===
* '''Arterial Septal Defect''' - type of congenital heart defect, whereby the blood flow between the left and right atria is through the interatrial septum
* '''Spina Bifida''' - type of developmental congenital disorder, whereby there is an incomplete closing of the embryonic neural tube.

--[[User:S8600021|Mark Hill]] 09:57, 3 August 2011 (EST) These answers are fine.

--[[User:Z3290841|z3290841]] 11:52, 4 August 2011 (EST)

==Lab 2 Assessment==
===Identify the ZP protein that spermatozoa binds and how is this changed (altered) after fertilisation===

'''Zona Pellucida Protein 3 (ZP3)''' is the glycoprotein where spermatozoa binds to, triggering an acrosome reaction that releases lytic enzymes, like acrosin and glycosidases. This aids in the movement of the sperm through Zona Pellucida. The ZP3 protein losses its ability to induce acrosome reaction and receive sperms once fertilisation occurs.

----
===Identify a review and a research article related to your group topic===

I did research on Cystic fibrosis and these are the 2 articles that I found that explains a lot about the disease, and the genetic research on it.

Review Article:

'''Cystic Fibrosis: Seminar'''

Description: This is basically outlining the pathophysiology of the disease, disease manifestation,current treatments diagnostic tool.

Ratjen F & Doring G.(2003).Cystic Fibrosis: Seminar.''The Lancet'', 361, 681-9. Retrieved from http://www.sciencedirect.com/science/article/pii/S0140673603125676

Research Article:

'''Gene expression profile study in CFTR mutated bronchial cell lines'''

Description: This article provides information about the severity of gene expression in relation of the extent or type of mutation.

Gambardella S, Biancolella M, D'Apice M, Amati F, Sangiuolo F, Farcomenti A, Chillemi G, Bueno S, Desideri A & Novelli G.(2006).Gene expression profile study in CFTR mutated bronchial cell lines.''Clinical and Experimental Medicine '', 6, 157-65. Retrieved from http://proquest.umi.com/pqdlink?Ver=1&Exp=08-05-2016&FMT=7&DID=1187181501&RQT=309&cfc=1

--z3290841 20:05, 10 August 2011 (EST)

--z3290841 11:10, 11 August 2011 (EST)

[[File:Differentially expressed RefSeq genes in human trisomy 21.jpg|thumb|Differentially expressed RefSeq genes in human trisomy 21]]

==Lab 3 Assessment==
===What is the maternal dietary requirement for late neural development===

====Iodine====
Dietary Requirement = 0.22 mg daily

Food Source = Seafood and iodized salt

Role = Important in the production of maternal thyroid hormone, which is not only needed by the mother but also by the developing fetus. This is because of its role in neuronal migration and myelination. Lack of iodine, thus thyroid hormone, may lead to cretinism, which is a syndrome characterised by permanent brain damage and mental retardation.

For more information see: http://www.pronutrition.org/files/MaternalNutritionDietaryGuide.pdf

====Omega-3 fatty acid DHA====
Dietary Requirement > 300 mg daily

Food Source = pink salmon, white tuna

Role = an essential fatty acid that promotes neural stem cell differentiation into neurons. This is by prompting cell cycle exit and suppressing cell death

====Folic Acid====
Dietary Requirement = 0.4 mg daily

Food source = dark green leafy vegetables, breakfast cereals, beans (legumes), whole grains

Role = Consumption reduces the risk of infant neural tube defects because it is an essential component for producing follate which is needed in DNA synthesis.

====Zinc====
Dietary Requirement > 11 mg daily

Food Source = Organ meats, red meat, poultry, whole fish

Role = It is said to have a role in the absorption of folic acid, thus lack of it may also lead to neural tube defects.

----

===Upload a picture relating to you group project===

'''Tetralogy of Fallot'''

[[File:Right ventricle of heart with Tetralogy of Fallot.jpg]]

--z3290841 11:14, 15 August 2011 (EST)

--[[User:Z3290841|z3290841]] 12:59, 18 August 2011 (EST)

==Lab 4 Assessment==

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

The allantois arises from the posterior part of the yolk sac. After the development of the hind-gut, around week 4-5, it is continuous with the cloaca, which is the terminal part of the hind-gut. It also moves closer to the umbilical vessels and becomes part of the umbilical cord.

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

#'''Ductus Venosus''' - connects the portal and umbilical veins to the inferior vena cava
#'''Ductus Arteriosus''' - connects pulmonary trunk to aorta
#'''Foramen Ovale''' - connects right and left atrium

===Identify the Group project sub-section that you will be researching===

*Introduction
*History
*Epidemiology
*Signs and Symptoms
*Genetics/Aetiology
*Pathophysiology and Abnormalities
*Diagnostic Tests
*Treatment/Management
*Prognosis
*Future Directions
*References

--[[User:Z3290841|z3290841]] 08:40, 24 August 2011 (EST)

--[[User:Z3290841|z3290841]] 12:49, 25 August 2011 (EST)

==Lab 5 Assessment==

===Which side (L/R) is most common for diaphragmatic hernia and why===
One of the developmental abnormalities of the diaphragm is Congenital Diaphragmatic Hernia (CDH), and a left sided Bochdalek hernia is the most common type of the abnormality. This means that the herniation occurs at the postero-lateral area of the diaphragm. The early closure of the right pluroperitoneal opening might be the cause as to why a left-sided CDH is more common.

--[[User:Z3290841|z3290841]] 08:20, 1 September 2011 (EST)

--[[User:Z3290841|z3290841]] 11:22, 1 September 2011 (EST)

==Lab 6 Assessment==

===What week of development do the palatal shelves fuse===
The palatal shelves fuse during the 9th Week of embryonic development. This involves the growth, elevation and fusion of primary palate, and then fusion with the secondary palate<ref>http://embryology.med.unsw.edu.au/embryology/index.php?title=Palate_Development</ref>.

===What early animal model helped elucidate the neural crest origin and migration of neural crest cells===
The quail-chick chimera was the early animal model used by Nicole Le Douarin to elucidate this. This is by grafting a neural crest tube and cells in the host chick's embryo. This is because Le Dourin have identified that a stain called the Fuelgen stain is ale to distinguish the cell form quail and chick<ref>http://www.sdbonline.org/archive/dbcinema/ledouarin/ledouarin.html</ref>.

===What abnormality results from neural crest not migrating into the cardiac outflow tract===
Some of these abnormalities include:
*Persistent Truncus Arteriosus (PTA)
*Double outlet right ventricle (DORV)
*Dextraposed aorta (DA)
*Tetralogy of Fallot (TOF)
*Ventricle septum defect (VSD)
Eperiments on mouse showed that partial ablation of cardiac neural crest results to DORV, DA, TOF and VSD, while PTA is the result of complete ablation of cardiac neural crest<ref>http://cardiovascres.oxfordjournals.org/content/47/2/212.full</ref>.

--[[User:Z3290841|z3290841]] 08:21, 15 September 2011 (EST)

--[[User:Z3290841|z3290841]] 11:08, 15 September 2011 (EST)

==Lab 7 Assessment==

===Are satellite cells (a) necessary for muscle hypertrophy and (b) generally involved in hypertrophy===
According to studies on satellite cells, they are not necessary for muscle hypertrophy, but they still undergo hypertrophy. This is why in the experimental studies of skeletal muscle the results showed that the muscle being studied underwent hypertrophy even though satellite cells have been deactivated. At the same time in another experiment where satellite cells haven't been deactivated, the muscle cells have increased in number, which is double the amount compared to when satellite cells are deactivated. This illustrates the ability of satellite cells to hypertrophy.

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

Chronic low frequency stimulation mimics the slow electrical signalling of motor neurons. Slow fibre muscles are more sensitive and responsive to these types of signals. Studies conducted investigating types of muscle fibres and conversion of the fibres to different types illustrated that these electrical stimulation/signals have the ability to transform/convert fast muscle fibres to slow muscle fibres. This is because chronic stimulation of fast fibres by low frequency signals activates an adaptive response that converts the muscle fibre, but the conversion follows the "next neighbour" rule, whereby the muscle fibres get converted in stages from a fast muscle fibre type to a slow muscle fibre type. It follows the following sequence of fibre types, from fastest to slowest type:
*IIb
*IIx
*IIa
*I
Also note that it could go from slow to fast fibres as well.

===Trisomy 21 page Evaluation===

Good brief and concise introduction. The use of the links at the end of the introduction is very helpful as the reader doesn't have to go back and fort if a section for external links was just made, but I believe there are too many links to put in one section, especially the introduction, it makes the section too cluttered and busy. I believe some of the links could be reevaluated and see if they should be incorporated in the page/section.

The recent findings section was an amazing idea, as it allows the reader to see that there are current progress on the disease, and it also gives credibility to the page as being up-to-date with the information.

I believe the karyotyping, aneuploidy, and Meiosis 1 & 2 section can be combined together as 1 subheading talking about the genetics/aetiology of the disease, which is not really explored in the page. It would have been much more informative if the page discussed about the current theories as to how the aneuploidy occurred, and use the Meiosis 1 & 2 section as back up evidence for it. Basically some of the sections are informative but not really necessary, like the Aneuploidy section, and it would have been better if the genetics side of things have been further explored.

The associated congenital abnormalities, heart defect and limb defect could have been synthesised together and presented in a much more conducive way, where the information is organised in a more orderly fashion, like the use of subheadings. The information contained in each of the 3 sections mentioned above have enough detail to get an idea about the defects in the disorder.

The section American College of Obstetricians and Gynecologists Recommendations and Trisomy growth charts could be interchanged, as it may allow the page to flow better than how it is.

The section of Prevalence and Diagnosis are done very well and are very informative.

The images and diagrams are used effectively throughout the whole page, there are no diagrams that should not be found in a section that it should not be in.

Overall it is a good page, not outstanding. It could still use some more information in it and the structuring could still be modified.

--[[User:Z3290841|z3290841]] 08:33, 22 September 2011 (EST)
--[[User:Z3290841|z3290841]] 11:58, 22 September 2011 (EST)

==Peer review:==

===Group 1===
*The introduction is good because it is brief and concise. Although it would have been good if the page actually introduced the headings that you guys have. It just allows the reader to find out what to expect on your page and if they need particular information they could just jump to that section. Also it didn’t really specify that the disease is a female only disease.
*The epidemiology section is fine and it lists the general occurrence of the disease. The graph used in the section is very effective in illustrating the observable malformations in the population. If there are more information about the demographics of the disease it would make this section better than what it is already. Some of the criticisms on this section are the use of the karyotyping image. I think the image is a bit out of place and should be placed in another section, and lastly it would also be helpful if some of the terms are defined within the section. The glossary section is good and all but, it just makes reading the page a bit more disjointed. I think the flow of the whole page would be better if the explanations of the terms are done immediately.
*The etiology section is straight to the point, descriptive and informative as well. The images are used effectively and they relate back to the information given. Only a criticism is the grammar of the section, it could be improved further. For example “When an uneven distribution is such that one of the gametes does not have any of a chromosome…” it doesn’t really flow or make sense. Also if the structuring of the whole section can just be revised a bit and clean up it would be near perfect.
*The clinical manifestation section is too much of a list; it is not very informative or descriptive at all. Even though each characteristics of the disease were referenced very well and the reader can immediately follow the link as to where more information could be found, it would probably have been preferable if at least the main clinical manifestations were defined and described here and explain how it is actually presented in the patient. Also an image in this section would not hurt.
*The diagnostic procedure of the page is done pretty well especially the table. The table was very effective and it summarized the basic diagnostic tools needed in the section. My only criticism for this section is that the very last sentence is a bit confusing, if you could just fix that up a bit. There are a lot of concepts being introduced in one paragraph that it becomes very confusing.
*Treatment section didn’t live up to its name unfortunately. Although there is one subsection (puberty and growth) that was very informative of the actual treatment for the disease, the rest are not very helpful at all. I guess some more research needs to be done for this section of the page.
*I really like the research part of the page because it tells you that your page is up-to-date and that your research is up-to-date as well. It gives the reader a sense of security that the data used are not old. The use of future research is also a great idea, although would have love to see some of the page creator’s own opinion about the future direction of this page, as it allows the reader to see that the creators of the page are also being critical of the disease.
*I am not really a big fan of glossaries. Although it is good that you guys incorporated that in the page, I personally am not a big fan of it as it makes the reading of the page a bit disjointed. If it is possible to avoid going to the glossary and just explain some of the words in context, I believe it will make the page much better.

===Group 2===
*The introduction is done quite well. It is succinct and brief. You have done a very good introduction to the topics that your page is about to explore. Unfortunately you did fail to introduce some of the headings that your page have, like the diagnostic section. Aside from this it is a good introduction overall.
*Historical background is done very well. It has enough detail to see the ongoing achievements on the disease.
*The epidemiology was excellent. You have covered the demography of the disease and properly cited some of the facts that you try to get across. Revision of some of the sentences may be needed because some sentences are not expressed properly. Also it would have been really nice if you could incorporate some of the data that was mentioned in a more summarized form, like a table, dot points, or something. It just makes reading easier and less likely to get lost in the words
*I really like how concise yet very informative your etiology section. What would make this section better than what it is at the moment is an image that would complement the information, and also a bit of an explanation about some of the terms that is in there, like “hemizygous”.
*The Pathogenesis section is very well done. It contains enough detail that we get an in-depth knowledge about the development of the disease, and the images that were used are very helpful. One thing that would improve it though is that if you can elaborate further on the function of the TBX1 gene and how affecting the expression of this gene results to DiGeorge.
*The Diagnostic test section I think is perfect. The way the test works was described, and at the same time they were all related back to how this aids in the detection of the disease. The layout of the information is also very engaging.
*Clinical manifestation is very nicely done. The information was very descriptive and informative. It is also presented very well. Just one thing though is that there is no clear separation between two clinical outcomes, so it tends to get confusing sometimes when someone is reading it. I guess adding more space between would be a good idea.
*Treatments section is done quite well. If you could add a video of some of these treatments or even just a link to a video of it that would really make this section perfect.
*The research section is also very good, especially your insight to future direction of research on this disease. I guess it wouldn’t hurt to drop some current research articles within this section, which shows the readers that the information that they have just read is up-to-date.
*Glossary is a good idea, not really a big fan of it but good idea anyway.

===Group 3===
*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

===Group 4===
*The introduction is very informative and actually introduced most of the subheadings that will be discussed in the page. The downfall of this introduction is the failure to introduce all of the sections of and proof-reading this section it is fine.
*The history of the disease is very well-done. The quick description or beginning of the history combined with the timeline is utilised well. Only improvement that would make it better is making the dates stand out by putting it I bold or something.
*I can find no fault in the epidemiology. It is the best one I have seen so far. You have described the demography of the disease and the statistics of other mutations. The tables were used appropriately as well, and the fact that it was described straight after the table is perfect.
*I like the genetics section of the page. It made sense and easy to understand. The diagrams are all relevant to the page section. Only criticism I can say is the description of the gene could probably be organised in a much simpler or better fashion, like a table, rather than just one whole sentence. Also I don’t know if it is typo or if that’s how you actually spell it, but I would just like to mention “Huntingtin gene”.
*The pathogenesis section is very informative of the disease. Unfortunately it is very disjointed. One idea was introduced after the other and they did not really connect properly. I think as the reader I am looking for some sort of direction that leads Huntington’s, like a step by step thing.
*I am assuming that the clinical manifestation is not yet finished, so I won’t say anything else other than change the positioning of the image to the other side because it breaks the page and it does not aid in getting the information across to your readers.
*The diagnostic test is a bit of a disappointment. I’m pretty sure that since it is a genetic disease there is some form of genetic testing that doctors can use to diagnose the onset of the disease, unless the etiology is still under debate and not sure of, and from what I have read from your page so far it is pretty definite that mutation in a particular gene is already implicated in the disease. So I think this section could probably do a lot more research and work.
*The video… section of your page is pointless, why isn’t this in the diagnostic section?? I think synthesizing both section is needed, as this section alone is pointless.
*The really like the table in the treatment section it is a a very good summary. If you could add the actual effect of each drugs to the patient, it would make this table better than what it actually is. The tetrabenzaine part is a bit out of place. If you are elaborating on the entire active chemical ingredients, I believe this is a good idea.
*I like the current and future research section of the page, as it informs the reader that the page is current and well informed about the recent endeavors on the disease. The only let down is that there is not a single research on finding a cure for the disease or looking for other treatments, which I think is one of the most popular topic on this disease. If you could add this in this section it would make this area much better. You could even add it in the treatment section.
*Not really a big fan of the glossary, but it is good idea anyway.

===Group 5===
*The information in the introduction is good but it is way too brief. The other section of the page was not introduced or not introduced properly, like the diagnosis section. Adding these bits would probably make the introduction good and a bit more informative as to what to expect from the page. Also reference them.
*The history I think is fine the way it is.
*The epidemiology is good because you have touched upon the demography of the disease and its prevalence. It would have been better if you could add a bit more statistics on the geographical distribution of the disease, as it makes the section more credible than how it already is. Unfortunately I think the section from “Screening… “ onwards is not very relevant for this section. I would consider revising as to where this information should be placed under. I guess this section needs more research overall.
*The etiology is very informative and I think you have gone in-depth in the topic, and is well researched, but I think it needs some revision. The concepts were far too technical and it makes the reader a bit too confused about what the information is actually saying. The images are amazing, and if you could incorporate them in the text it would make the section better.
*The development of the disease section I think should be the pathogenesis of the disease. This section was not done properly, as I was expecting to see how the etiology and all the clinical manifestations relate to each other; instead it was all about the clinical manifestation. I think you need to look further into this section.
*The signs and symptoms section is very informative, but I am questioning the information as it is not referenced at all in most of the paragraph.
*Diagnosis should probably changed to diagnostic tests because the diagnosis is Fragile X. The information is good for introducing the techniques to the reader. I think further description of the tests is needed.
The treatment section has some very good information on it that describes the treatments used for the disease. It could probably be better if you could highlight the actual treatments and make it stand out.
*Recent research is a bit disappointing because the most recent research that were presented is 3 years ago. As a reader, this makes me question the content of the page, whether it is up-to-date or not. It would also be good to have a more recent paper/research and the inclusion of future direction of this disease.

===Group 7===
*Introduction is too brief. It would be good if you could introduce the other headings that you guys have in your page.
History is informative and the timeline is a good summary of the history. It could be improved by adding an image of Dr angelman or something relevant to the section, also it you could make the dates in the timeline stand out more.
*I like the simplicity of the epidemiology. The use of an image would probably make this section better. Also if you could add a bit more statistics to this part, it would be more informative.
*Aetiology is not informative enough. I think you need to further research this section and add a bit more information about the mutations, and the table doesn’t really make a lot of sense as well.
*I really like the pathogenesis section. It is very informative and fully explains the disease process. The diagram that was used is very useful in understanding the disease process. Only criticism is that sometimes the paragraphs get out of hand and goes to verbose for the reader to understand. If you could elaborate further on the technical concepts it would help a lot.
*Fix up the heading. The table is a bit confusing when you first look at it. Aside from these 2 the information I think covers the idea of the signs and symptoms of the disease.
*I think the heading should be Diagnostic tests because the diagnosis is Angelman Syndrome. The flow diagram is good for this section and the information provided are all relevant. Just make sure to make the little headings bold and not italics, and not dot points as it makes it better.
*Treatment is summarized perfectly . I just think that you should make the left column bold.
*The genetic counseling section doesn’t make sense to me. I think you should at least have some description of this section and explain what it is for
*The current and future research could be further improved by actually mentioning current research being done (article names), and a future direction reflection would probably be good as well.

--[[User:Z3290841|z3290841]] 10:25, 29 September 2011 (EST)

attendance --[[User:Z3290841|z3290841]] 11:21, 6 October 2011 (EST)

==Lab 10 Assessment==

===Besides fetal alcohol syndrome, identify another environmental teratogen that can lead to hearing loss===
'''Thalidomide''' is an environmental teratogen that can be found in drugs that control nausea in the 1950s and was banned in 1961 because of all the birth defects that is associated with the drug. This includes hearing loss or the lack of development of the ear.

===Identify 3 factors that contribute to poor neonatal drainage of the middle ear===
The three factors that contribute to poor neonatal drainage of the middle ear includes:
*Size of the Eustachian tube
*Orientation of the Eustachian tube
*Muscles that opens up the Eustachian tube = only one in neonates (tensor palati) compared the 2 muscles in adult (tensor palati and levator palati)

===Identify 1 genetic abnormality that affects hearing development and link to the OMIM record===
One genetic abnormality would be in DIAPH1 gene of chromosome 5. This leads to Hereditary Low Frequency Hearing Loss. OMIM number [http://omim.org/entry/602121/ 602121]

Attendance lab 10: --[[User:Z3290841|z3290841]] 12:48, 13 October 2011 (EST)

==Lab 11 Online Assessment==
===Name the components that give rise to the interatrial septum and the passages that connect the right and left atria===
*Septum primum
*Septum Secundum
*Foramen secundum
*Foramen ovale

===Identify the cardiac defects that arise through abnormal development of the outflow tract===
*Tetralogy of Fallot
*Transposition of the Great Vessels
*Hypoplastic Left Heart Syndrome
*Double Outlet Right Ventricle

--[[User:Z3290841|z3290841]] 10:56, 20 October 2011 (EST)

Attendance: --[[User:Z3290841|z3290841]] 12:03, 20 October 2011 (EST)

==Lab 12 Online Assessment==
===Give examples of 3 systems that continue to develop postnatally===
*Central Nervous System - brain development
*Respiratory System - breathing mechanism (ribs orientation)
*Musculoskeletal system - bones still undergoing ossification, and also muscular development.

===Identify the abnormalities detected by the Guthrie Test and link to one abnormality listed in OMIM===
*Phenylketonuria (PKU)
*Hypothyroidism
*Cystic Fibrosis - OMIM number: [http://omim.org/entry/602421/ 602421]

User:Z3290841

2011-10-20T01:03:03Z

Z3290841:

User:Z3290841

2011-10-19T23:56:06Z

Z3290841:

2011 Group Project 6

2011-10-13T02:50:35Z

Z3290841: /* Pathophysiology and Abnormalities */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by one or more genetic mutation on different chromosomes, which includes chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

[[File:Cyanotic baby.jpg||200px|thumb|left|Image of a cyanotic baby]]Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 [[#Glossary | '''microdeletions''']] have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a [[#Glossary | '''transcription factor''']], it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a [[#Glossary | '''haploinsufficient gene''']]. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in [[#Glossary | '''exon''']] 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], [[#Glossary | '''ventricular''']] and [[#Glossary | '''conotruncal''']] septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a [[#Glossary | '''missesnse mutation''']] of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref name= Robbins><Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.></ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref name= Robbins/> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the pulmonary and subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected subclavian artery and the pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the subclavian artery to the pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the aorta (on the left side of chest) to the left branch of the pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the aorta, to the right branch of the pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the pulmonary artery, which is till connected to the main pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary |'''Transatrial''']]) or from the right atrium/from the pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed pulmonary blood vessels and the pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Allagile Syndrome''' - it is a neonatal genetic disorder, which results in liver disease with cholestasis, peripheral pulmonic stenosis and unusual face

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Artificial Ductus''' - it is an instrument inserted into blood vessels to create a channel that would allow blood to flow through.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''DiGeorge Syndrome''' - it is a congenital disorder which results from a microdeletion of the 22q11.2 region of Chromosome 22. It is characterised by hypocalcemia, immunodeficiency, and congenital heart disease.

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Electrocardiogram''' - it is a diagnostic procedure that detects the electrical activity of the heart.

'''Exon''' – coding region of DNA.

'''Flouroscope''' - an imaging instrument used in fluoroscopy, where an X-ray and a CCD video camera is used to obtain real time moving images.

'''Foramen Ovale''' - it is an anatomical channel found on the interatrial septum, which allows the blood to flow between atria in the developing baby.

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Heart Failure''' - condition where the heart is unable to supply blood to the whole body.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Patent Ductus Arteriosus''' - is a congenital condtion that causes the failure of the ductus arteriosus to close

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Stethoscope''' - an instrument used, especially by medical doctors, to hear ausculatory sounds made in the body, generally in the thoracic area.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Trisomy''' - it is a type of genetic mutation where there is an extra chromosome, in this case a total of 3.

'''Velocardiofacial Syndrome''' - is a syndrome that causes cleft palate, heart defects, abnormal facial structure and learning problems, which is due to a congenital malformation.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

* Heart development lectures showing the genetic influences to anomalies such as TOF
http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Heart_Development

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-13T02:44:54Z

Z3290841: /* Glossary */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by one or more genetic mutation on different chromosomes, which includes chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

[[File:Cyanotic baby.jpg||200px|thumb|left|Image of a cyanotic baby]]Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 [[#Glossary | '''microdeletions''']] have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a [[#Glossary | '''transcription factor''']], it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a [[#Glossary | '''haploinsufficient gene''']]. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in [[#Glossary | '''exon''']] 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], [[#Glossary | '''ventricular''']] and [[#Glossary | '''conotruncal''']] septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a [[#Glossary | '''missesnse mutation''']] of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Allagile Syndrome''' - it is a neonatal genetic disorder, which results in liver disease with cholestasis, peripheral pulmonic stenosis and unusual face

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Artificial Ductus''' - it is an instrument inserted into blood vessels to create a channel that would allow blood to flow through.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''DiGeorge Syndrome''' - it is a congenital disorder which results from a microdeletion of the 22q11.2 region of Chromosome 22. It is characterised by hypocalcemia, immunodeficiency, and congenital heart disease.

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Electrocardiogram''' - it is a diagnostic procedure that detects the electrical activity of the heart.

'''Exon''' – coding region of DNA.

'''Flouroscope''' - an imaging instrument used in fluoroscopy, where an X-ray and a CCD video camera is used to obtain real time moving images.

'''Foramen Ovale''' - it is an anatomical channel found on the interatrial septum, which allows the blood to flow between atria in the developing baby.

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Heart Failure''' - condition where the heart is unable to supply blood to the whole body.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Patent Ductus Arteriosus''' - is a congenital condtion that causes the failure of the ductus arteriosus to close

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Stethoscope''' - an instrument used, especially by medical doctors, to hear ausculatory sounds made in the body, generally in the thoracic area.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Trisomy''' - it is a type of genetic mutation where there is an extra chromosome, in this case a total of 3.

'''Velocardiofacial Syndrome''' - is a syndrome that causes cleft palate, heart defects, abnormal facial structure and learning problems, which is due to a congenital malformation.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

* Heart development lectures showing the genetic influences to anomalies such as TOF
http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Heart_Development

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-13T02:28:44Z

Z3290841: /* Glossary */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by one or more genetic mutation on different chromosomes, which includes chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 [[#Glossary | '''microdeletions''']] have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a [[#Glossary | '''transcription factor''']], it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a [[#Glossary | '''haploinsufficient gene''']]. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in [[#Glossary | '''exon''']] 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], [[#Glossary | '''ventricular''']] and [[#Glossary | '''conotruncal''']] septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a [[#Glossary | '''missesnse mutation''']] of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Allagile Syndrome''' -

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Artificial Ductus''' -

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''DiGeorge Syndrome''' -

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Electrocardiogram''' -

'''Exon''' – coding region of DNA.

'''Flouroscope''' -

'''Foramen Ovale''' - it is an anatomical channel

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Heart Failure''' - condition where the heart is unable to supply blood to the whole body.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Patent Ductus Arteriosus''' - is a congenital condtion that causes the failure of the ductus arteriosus to close

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Stethoscope''' - an instrument used, especially by medical doctors, to hear ausculatory sounds made in the body, generally in the thoracic area.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Trisomy''' - it is a type of genetic mutation where there is an extra chromosome, in this case a total of 3.

'''Velocardiofacial Syndrome''' - is a syndrome that causes cleft palate, heart defects, abnormal facial structure and learning problems, which is due to a congenital malformation.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

* Heart development lectures showing the genetic influences to anomalies such as TOF
http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Heart_Development

==References==

<references/>

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=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by one or more genetic mutation on different chromosomes, which includes chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 [[#Glossary | '''microdeletions''']] have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a [[#Glossary | '''transcription factor''']], it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a [[#Glossary | '''haploinsufficient gene''']]. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in [[#Glossary | '''exon''']] 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], [[#Glossary | '''ventricular''']] and [[#Glossary | '''conotruncal''']] septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a [[#Glossary | '''missesnse mutation''']] of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Exon''' – coding region of DNA.

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

* Heart development lectures showing the genetic influences to anomalies such as TOF
http://embryology.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Heart_Development

==References==

<references/>

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=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by one or more genetic mutation on different chromosomes, which includes chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 [[#Glossary | '''microdeletions''']] have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a [[#Glossary | '''transcription factor''']], it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a [[#Glossary | '''haploinsufficient gene''']]. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in [[#Glossary | '''exon''']] 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], [[#Glossary | '''ventricular''']] and [[#Glossary | '''conotruncal''']] septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a [[#Glossary | '''missesnse mutation''']] of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Exon''' – coding region of DNA.

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

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=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by one or more genetic mutation on different chromosomes, which includes chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 [[#Glossary | '''microdeletions''']] have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a [[#Glossary | '''transcription factor''']], it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a [[#Glossary | '''haploinsufficient gene''']]. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in [[#Glossary | '''exon''']] 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], [[#Glossary | '''ventricular''']] and [[#Glossary | '''conotruncal''']] septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 3 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a [[#Glossary | '''missesnse mutation''']] of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Exon''' – coding region of DNA.

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

User:Z3290841

2011-10-12T23:22:27Z

Z3290841: /* Identify 1 genetic abnormality that affects hearing development and link to the OMIM record */

User:Z3290841

2011-10-12T23:22:01Z

Z3290841:

2011 Group Project 6

2011-10-12T23:10:24Z

Z3290841: /* Introduction */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by one or more genetic mutation on different chromosomes, which includes chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 [[#Glossary | '''microdeletions''']] have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a [[#Glossary | '''transcription factor''']], it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a [[#Glossary | '''haploinsufficient gene''']]. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in [[#Glossary | '''exon''']] 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], [[#Glossary | '''ventricular''']] and [[#Glossary | '''conotruncal''']] septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a [[#Glossary | '''missesnse mutation''']] of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Exon''' – coding region of DNA.

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T14:40:45Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 [[#Glossary | '''microdeletions''']] have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a [[#Glossary | '''transcription factor''']], it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a [[#Glossary | '''haploinsufficient gene''']]. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in [[#Glossary | '''exon''']] 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], [[#Glossary | '''ventricular''']] and [[#Glossary | '''conotruncal''']] septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a [[#Glossary | '''missesnse mutation''']] of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Exon''' – coding region of DNA.

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T14:33:10Z

Z3290841: /* Glossary */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a '''haploinsufficient gene'''. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in exon 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a '''missesnse mutation''' of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Conotruncal septation''' – it is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Exon''' – coding region of DNA.

'''Haploinsufficient gene''' – it is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Microdeletion''' - it is a mutation whereby a small part of the chromosome/DNA sequence is omitted.

'''Missense mutation''' – it is a point mutation, whereby a single nucleotide has been changed resulting to a different codon that will lead to the formation of a different amino acid.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''Transcription factor''' - it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes.

'''Ventricular Septation''' – it is the formation of the interventricular septum in the adult heart, which separates the left and right ventricle.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

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=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a '''haploinsufficient gene'''. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in exon 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of [[Development Animation - Heart Atrial Septation|atrial]], ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a '''missesnse mutation''' of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases ventilator drive. <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:The Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something deviating from normal

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease/physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity.

'''Intravenous''' - inside veinous structures.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - care that focuses on relieving the suffering of patients rather than treating it.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T13:29:31Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a '''haploinsufficient gene'''. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in exon 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

'''OMIM number''' = [http://omim.org/entry/602054?search=TBX1&highlight=tbx1/ 602054]

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

'''OMIM number''' = [http://omim.org/entry/600584/ 600584]

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a '''missesnse mutation''' of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

'''OMIM number''' = [http://omim.org/entry/601920/ 601920]

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - inside veinous structures.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative''' - care that focuses on relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T13:22:12Z

Z3290841: /* Other Genes */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a '''haploinsufficient gene'''. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in exon 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a '''missesnse mutation''' of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

===Other Genes===
These are the other mutated genes that are found in TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - inside veinous structures.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative''' - care that focuses on relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T13:19:52Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a '''haploinsufficient gene'''. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in exon 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a '''missesnse mutation''' of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

===Other Genes===
These are the other genes that had a mutation that were found in other TOF patients:

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Other Genes'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Gene'''
|align="center"|''' Location'''
|align="center"|'''Protein Product'''
|align="center"|'''Gene MIM number'''
|-
|align="center"|'''ZFPM2'''
|align="center"| 8q23.1
|align="center"| Zinc Finger Protein
|align="center"| [http://omim.org/entry/603693/ 603693]
|- style="background:#eeeeff"
|align="center"|'''GDF1'''
|align="center"| 19p13.11
|align="center"| Growth/Differentiation Factor 1
|align="center"| [http://omim.org/entry/602880/ 602880]
|-
|align="center"|'''CITED2'''
|align="center"| 6q24.1
|align="center"| CBP/p300-Interacting Transactivator, with GLU/ASP-rich C-Terminal Domain 2
|align="center"| [http://omim.org/entry/602937?search=Cited2&highlight=cited2/ 602937]
|- style="background:#eeeeff"
|align="center"|'''GATA4'''
|align="center"| 8p23.1
|align="center"| GATA-binding protein 4
|align="center"| [http://omim.org/entry/600576?search=gata4&highlight=gata4/ 600576]
|-
|align="center"|'''NOTCH2'''
|align="center"| 1p12-p11
|align="center"| NOTCH2 receptor protein
|align="center"| [http://omim.org/entry/600275?search=notch2&highlight=notch2/ 600275]
|- style="background:#eeeeff"
|align="center"|'''NOTCH1'''
|align="center"| 9q34.3
|align="center"| NOTCH1 receptor protein
|align="center"| [http://omim.org/entry/190198?search=notch%201&highlight=1%20notch/ 190198]

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute cyanosis usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] morphine provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*Asymptomatic patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a [[#Glossary | '''palliative''']] method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the [[#Glossary | '''hypertrophy''']] of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made between adjacent blood vessels.

'''Annular hypoplasia''' – A ring shaped underdevelopment of tissue/organs

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - deoxygenated blood returning to the heart is diverted to a machine which oxygenated the lung and then pumps it to the arterial system.

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - inside veinous structures.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative''' - care that focuses on relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve cannot prevent back flow of blood.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - a Coagulation or clotting in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

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2011 Group Project 6

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=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a '''haploinsufficient gene'''. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in exon 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene '''Jagged-1 protein (JAG1 protein)''', which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a '''missesnse mutation''' of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute [[#Glossary | '''cyanosis''']] usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] [[#Glossary | '''morphine''']] provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*[[#Glossary | '''Asymptomatic''']] patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a palliative method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the hypertrophy of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) [Xu H, Baldini A (2007) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made surgically between adjacent blood vessels.

'''Annular hypoplasia''' – (need definition)

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Asymptomatic''' - producing or showing no symptoms.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - Blood returning to the heart is diverted through a heart-lung machine (a pump-oxygenator) before returning it to the arterial circulation. The machine does the work both of the heart (pump blood) and the lungs (supply oxygen to red blood cells).

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - existing or taking place, within veins.

'''Morphine''' - an analgesic and narcotic drug obtained from opium and used medicinally to relieve pain.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - Healthcare that focuses on preventing and relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve is not strong enough to prevent the back flow on blood into the right ventricle.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - local coagulation or clotting of the blood in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T12:26:05Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of '''Tetralogy of Fallot (TOF)''' is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for '''T-box 1 transcription factor (TBX1)'''. As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a '''microdeletion of 3 or 1.5 Mb of 22q11.2''' region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a '''haploinsufficient gene'''. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a '''30-bp duplication in exon 9c''', a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is '''dose-dependent''', which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the '''NK2 homeobox 5 transcription factor (NKX2-5 protein)'''. NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene Jagged-1 protein (JAG1 protein), which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a '''missesnse mutation''' of the JAG1 gene identified at the 821st base pair. This is a G to A base substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute [[#Glossary | '''cyanosis''']] usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] [[#Glossary | '''morphine''']] provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*[[#Glossary | '''Asymptomatic''']] patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a palliative method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the hypertrophy of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) [Xu H, Baldini A (2007) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made surgically between adjacent blood vessels.

'''Annular hypoplasia''' – (need definition)

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Asymptomatic''' - producing or showing no symptoms.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - Blood returning to the heart is diverted through a heart-lung machine (a pump-oxygenator) before returning it to the arterial circulation. The machine does the work both of the heart (pump blood) and the lungs (supply oxygen to red blood cells).

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - existing or taking place, within veins.

'''Morphine''' - an analgesic and narcotic drug obtained from opium and used medicinally to relieve pain.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - Healthcare that focuses on preventing and relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve is not strong enough to prevent the back flow on blood into the right ventricle.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - local coagulation or clotting of the blood in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T12:12:07Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of Tetralogy of Fallot (TOF) is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for T-box 1 transcription factor (TBX1). As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a microdeletion of 3 or 1.5 Mb of 22q11.2 region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a haploinsufficient gene. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a 30-bp duplication in exon 9c, a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is dose-dependent, which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the NK2 homeobox 5 transcription factor (NKX2-5 protein). NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene Jagged-1 protein (JAG1 protein), which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a missesnse mutation of the JAG1 gene identified at the 821st base pair. This is a G to A substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute [[#Glossary | '''cyanosis''']] usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] [[#Glossary | '''morphine''']] provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*[[#Glossary | '''Asymptomatic''']] patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a palliative method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the hypertrophy of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) [Xu H, Baldini A (2007) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made surgically between adjacent blood vessels.

'''Annular hypoplasia''' – (need definition)

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Asymptomatic''' - producing or showing no symptoms.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - Blood returning to the heart is diverted through a heart-lung machine (a pump-oxygenator) before returning it to the arterial circulation. The machine does the work both of the heart (pump blood) and the lungs (supply oxygen to red blood cells).

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - existing or taking place, within veins.

'''Morphine''' - an analgesic and narcotic drug obtained from opium and used medicinally to relieve pain.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - Healthcare that focuses on preventing and relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve is not strong enough to prevent the back flow on blood into the right ventricle.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - local coagulation or clotting of the blood in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

Talk:2011 Group Project 6

2011-10-12T12:11:25Z

Z3290841:

[[2011_Group_Project_6|'''Group 6''']]: [[User:z3290841]] | [[User:z3291317]] | [[User:z3291324]] | [[User:z3291423]]

{{2011GroupDiscussionMH}}

Slowly as in bit by bit, which is now done, look at it and see if you still don't understand what it's talking about. I tried to clarify some of the things that I think needs to be clarified. Also I don't know how to put a title on

what do you mean you'll slowly change it? its due in 12 hrs! (z3291324)

Ok this is going to be the new outline of the genetics part, I'll slowly change it here in the discussion so things will be added along the way, also Z3291324 the comments said table, but I'm not planning to put all my info in a table, just the gene profile, the rest will be in text form cause I don't think the information will come across better if I put all of it in a table.

==Genetics/Aetiology==

The genetic etiology of Tetralogy of Fallot (TOF) is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for T-box 1 transcription factor (TBX1). As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a microdeletion of 3 or 1.5 Mb of 22q11.2 region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a haploinsufficient gene. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a 30-bp duplication in exon 9c, a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is dose-dependent, which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|Chromosome 5 - NKX2-5 Gene|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the NK2 homeobox 5 transcription factor (NKX2-5 protein). NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|Chromosome 20 - JAG1 gene|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene Jagged-1 protein (JAG1 protein), which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a missesnse mutation of the JAG1 gene identified at the 821st base pair. This is a G to A substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

what does everyone think?
http://www.youtube.com/watch?v=_ErZG43lAh8&feature=related at 51 seconds (for physical examination pathophys table) --[[User:Z3291324|z3291324]] 11:24, 11 October 2011 (EST)
actually, this one is probably better http://www.youtube.com/watch?v=3bN7QltwfB0&feature=related at 5 seconds

does anyone know how to properly reference a book? i used robbins basic pathology for some of the pathophys section but im not sure how to reference it--[[User:Z3291324|z3291324]] 11:01, 11 October 2011 (EST)

hey rommel, are you putting these pics on the page? also, can you check out the feedback for your section...did other groups recommend a table for the genetics..or getting rid of the dot points? pics look good btw --[[User:Z3291324|z3291324]] 10:07, 11 October 2011 (EST)

Finally the last image for genetics. That should be it for now I'm really tired. I'll update and clear up the text on the page tomorrow, hopefully you made a comment on the timages and table by then, if not that's fine, but I won't put it in the page until I get a general consensus. --[[User:Z3290841|z3290841]] 19:50, 6 October 2011 (EST)

[[File:Chromosome 20 - JAG1 gene.jpg]]

Here I have another image for the next gene --[[User:Z3290841|z3290841]] 17:51, 6 October 2011 (EST)

[[File:Chromosome 5 - NKX2-5 Gene.jpg]]

Ok guys here you go I changed the image again, hopefully it's better if not tell me asap so I can change it --[[User:Z3290841|z3290841]] 16:36, 6 October 2011 (EST)

[[File:Chromosome 22 - TBX1 Gene.jpg]]

Hey I changed the table for genetics up tell me what you think. If it's good for you guys I'll be putting it in the page. --[[User:Z3290841|z3290841]] 16:02, 6 October 2011 (EST)

Just put up some internal links on the page. feel free to add or remove what you thin is necessary. these are th eones that i just put up
Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21
--[[User:Z3291324|z3291324]] 11:35, 6 October 2011 (EST)

Hey this is just a trial run for the table I am doing for the genetics part of our page --[[User:Z3290841|z3290841]] 11:17, 6 October 2011 (EST)

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22
|align="center"| 5
|align="center"| 20
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

Hey Rom and jaq, thanks for fixing up the table! :-{) --[[User:Z3291317|Z3291317]] 10:42, 6 October 2011 (EST)

Hey I editted the one that jaqui editted

{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

Hey guys, I'm currently editing through my sections and adding new stuff, also check the image i placed in the diagnostic techniques part under MRI, i hope it fits properly! also rom the diagram looks a bit complicated, could you simplify it and explain what you are trying to show? thanks --[[User:Z3291423|Jasjit Walia]] 00:53, 6 October 2011 (EST)

test:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

Hey People i re tweaked the table to rom's preferences, and rom you slightly jumbled the structure of the entire table, so i fixed it. Also, in your diagram, it was a bit hard trying to understand the part you try to demonstrate the zone being deleted. Speak to you about it later. Regards --[[User:Z3291317|Z3291317]] 22:50, 5 October 2011 (EST)

Hey guys I just fixed up bits and pieces of the dates on the timeline. Jaqui the table looks really good, and uhm I think I prefer the coplour of jaqui's table. The red looks a but eh to me. By the way thanks furkan for fixing the tables up now all it needs is the reference and I think we can start to get rid of some of the things in the history. Also I made a diagram for genetics so have a geez and tell me things that you like and don't like and/or hate. Also Jaqui I found a yoputube video for your MRI section of the heart I really don't understand what it's showing but I think it'll be really good if we can imbed it and keep it on loop, here's the link http://www.youtube.com/watch?v=UZk9ForCPyE --[[User:Z3290841|z3290841]] 16:30, 5 October 2011 (EST)

[[File:TBX1 gene.jpg]]

just testing out jaz's table too. i think i might have accidentally done this one in blue too --[[User:Z3291324|z3291324]] 21:27, 3 October 2011 (EST)

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the defending portion of the aorta (on the left side of chest) to the left branch of the pulmonary artery. <ref>http://www.chdinfo.com/aa/aa112397.htm</ref>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the pulmonary artery and it is also very hard to close when complete repair is undertaken <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the aorta, to the right branch of the pulmonary. <ref>http://www.chdinfo.com/aa/aa112397.htm</ref>
| This shunt’s use is more suited to those with pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have with the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right pulmonary artery (the classic Glenn shunt). The modified glenn shunt is for, the superior vena cava to the right branch of the pulmonary artery, which is till connected to to the main pulmonary artery.<ref>http://www.chdinfo.com/aa/aa112397.htm</ref>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
|- style="background:#eeeeff"
|}

for the intro, did we decide to make it like a summary of whats to come (so include a bit of epidemiology, symptoms, treatment etc)??--[[User:Z3291324|z3291324]] 21:16, 3 October 2011 (EST)

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with ''cyanosis'' and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|Insert physical examination image

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions.
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh ''systolic ejection murmur'' may be heard and a palpable thrill may be felt along the left sternal border. These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>

|Insert heart murmur image

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device.
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|Insert electrocardiogram image here

|- style="background:#eeeeff"
|align="Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
|[[File:echo.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray.
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|Insert MRI image here
|- style="background:#eeeeff"
|}
--[[User:Z3291324|z3291324]] 20:29, 3 October 2011 (EST)

Hey Jaq, here is the proposed final table without the references (will be added later). When you have the top part dark red, the reader will cognitively look at the lighter colour as red as the brain will be using the darker colour as a comparative standard (i know its a bit far fetched explanation), i think it will be alright having the colours like this... Look at the new table below, i had fixed some dates up rommel thought were together as it appeared like that in the text, so fiddled with them a bit and added some important dates i should had from before, so this new info would only be found in the table and not in the text, what you guys think?....--[[User:Z3291317|Z3291317]] 19:44, 3 October 2011 (EST)

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”
|-
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart.
|- style="background:#eeeeff"
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7
|-
|align="center"|'''1943'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells.
|- style="background:#eeeeff"
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|-
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery
|- style="background:#eeeeff"
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery
|-
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant.
|- style="background:#eeeeff"
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot
|-
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants.
|}

hey furkan, thanks heaps for trying with the table. what do you guys think? maybe our colour scheme would be better as blue and grey. do you think the red looks a bit pink?? --[[User:Z3291324|z3291324]] 19:34, 3 October 2011 (EST)

Hey People i took on Jaq ideas and reformatted the table Rom made (thanks rom!). Its still a work in progress as im going to add many more dates into it so it can accompany the text in the history without having to remove the text. Man coding is annoying lol... regards --[[User:Z3291317|Z3291317]] 18:28, 3 October 2011 (EST)

{| style="border: solid 1px #e75269"
|- align="center" style="background:#f30d39"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot
|- style="background:#ffeeee"
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot.
Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology
|-
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”
|- style="background:#ffeeee"
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7
|-
|align="center"|'''1943'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells.
|- style="background:#ffeeee"
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|- style="background:#ffeeee"
|align="center"|'''1950'''
| rise of open heart surgery
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery
|- style="background:#ffeeee"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant.
Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants.
|- style="background:#ffeeee"
|}

hey rommel! love the table! but are we going to have the table as well as the text? any chance you could make the blue a ligth red..but keep it really similar ie the darker red at the top with the light red and white in the table (so it matches the rest of the colour scheme)--[[User:Z3291324|z3291324]] 17:34, 3 October 2011 (EST)

Hey this is my attempt at making the timeline for the history section. I haven't put in any references cause I just want to check on the things that I put in it if you guys would agree. Feel free to change it, delete some of it and add some stuff in it. Also I just copied the table template from some other group so yeah :)

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot
|- style="background:#eeeeff"
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot.
Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology
|-
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”
|- style="background:#eeeeff"
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7
|-
|align="center"|'''1943'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells.
|- style="background:#eeeeff"
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|- style="background:#eeeeff"
|align="center"|'''1950'''
| rise of open heart surgery
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant.
Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants.
|- style="background:#eeeeff"
|}

'''Summary of the Comments made on our draft project'''

- Intro = add picture and basically fix it up
- History = put the quote in the box, add a timeline and less word, put the dates in bold
- Epidemiology = more detail and work
- Signs and symptoms = better ghlossary, change the size of subheadings, explain further, picture for each signs and symptoms
- Genetics = explain better, i.e. the technical details, add a table
- Pathophysiology = reformat
- Prognosis = add a pie chart
- Future Directions = add articles
- Glossary - make some links

here youi go guys, sorry it's a bit late --[[User:Z3290841|z3290841]] 09:44, 3 October 2011 (EST)

hey fru, okay. maybe we should go for alternating colours then. ill try out a couple tonight. also, im just pasting the intro here on the discussion page because im going to edit it either tonight or tomorrow --[[User:Z3291324|z3291324]] 21:24, 2 October 2011 (EST) I like the grey and red border you put around the quote. maybe we can make our colour scheme gray and red. can you try and put that same colour grey into every second box of the diagnostic table. i tried to put in red and grey but for some reason it keeps turning different shades of green!--[[User:Z3291324|z3291324]] 21:46, 2 October 2011 (EST)

Tetralogy of Fallot (TOF), named after Etienne Fallot is a disease that occurs in 3 in every 10000 live births and constitutes to roughly 7%-10% of all cardiac congenital defects today.
TOF is believed to occur due to genetic mutation, which is thought to impact on the development upon the neonate heart. Furthermore, it is believed that the genetic aetiology of TOF is a mutation in one of chromosomes 5,20 and 25. These genetic mutations contribute to the four characteristic defects, in the heart of a patient having TOF:
Pulmonary stenosis
Overiding aorta
Ventricular septal defect
Right ventricular hypertrophy
TOF patients are nicknamed 'Blue babies' because the lack of oxygen being supplied to the body. Some common occurrences for TOF patients include, Infants turning blue when crying, children collapsing due to tet spells during exercise and fatigue.
Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the scientific community's understanding of the cardiac anomaly and ways to treat it. Today, surgery remains the only way to treat the anomaly, however palliative care and medical treatment is available.
Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.
Whilst a lot of knowledge is available on this disease, future directions include developing durable and efficient surgical procedures, shunts and valves.

REPLY 2: You can have the old format, ot have the red and white osscilating colours for the rows, or have both with the borders not that prominent and have the colour changes in the table. Ye i relised your pic was put down, well discuss it at next lab. hows finding other pics going?--[[User:Z3291317|Z3291317]] 10:22, 2 October 2011 (EST)

Do you think the diagnostic table would look better in paragraphs? I think the table is a bit big?--[[User:Z3291324|z3291324]] 13:31, 1 October 2011 (EST)
REPLY: I reckon it will be okmto put into the table if you insert outlines into the table. If you put it into paragraphs, there is gonna be alot of writing in a section that, i think, the reader wouldnt want to read. It your call, see what the other 2 boys think --[[User:Z3291317|Z3291317]] 22:24, 1 October 2011 (EST) thanks fru, do you mean change it back to the old table format? or maybe we could put a light red background for every second row. (i tried doing that but i couldnt find a colour that was light enough and wasnt too pink). also, one of my pics got taken down so i wont upload any til the lab next thursday. --[[User:Z3291324|z3291324]] 08:40, 2 October 2011 (EST)

hey guys, ive fixed up the glossary up to treatment (but i havent done the genetics part). the terms in glossary are in bold at the moment but anyone feel free to change them to a link or anything else.--[[User:Z3291324|z3291324]] 12:48, 1 October 2011 (EST)

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_6_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_6_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

Test table --[[User:Z3291324|z3291324]] 19:02, 30 September 2011 (EST)
{|
|-bgcolor="# AEF572"
| '''Diagnostic technique
| '''How it works'''
| '''Presentation in a TOF patient'''
|'''Image'''
|-
| Physical examination
|TOF is often diagnosed during fetal life by echocardiography (Apitz, Webb, & Redington, 2009). If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with cyanosis and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. (Somerville, 1993)
|Insert physical examination image
|-
|Heart murmurs
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions.
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh systolic ejection murmur may be heard and a palpable thrill may be felt along the left sternal border. These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). http://ccjm.org/content/77/11/821.full
|Insert heart murmur image
|-
|Electrocardiogram
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device.
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.(Somerville, 1993)
|Insert electrocardiogram image here
|-
|Chest radiograph
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnoses many conditions including the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. (Bailliard & Anderson, 2009) The radiograph will also show a right-sided aorta in approximately one-quarter of patients. (Somerville, 1993)
|[[File:Chestxrayfallot.jpg|200px]]
|-
|Echocardiogram
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. (Bailliard & Anderson, 2009)
|[[File:echo.jpg|200px]]
|-
|Magnetic resonance imaging
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray.
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect. (Somerville, 1993)
|Insert MRI image here
|-
|}

Test:
<object width="480" height="360"><param name="movie" value="http://www.youtube.com/v/PRxN6migkW8?version=3&hl=en_US"></param><param name="allowFullScreen" value="true"></param><param name="allowscriptaccess" value="always"></param><embed src="http://www.youtube.com/v/PRxN6migkW8?version=3&hl=en_US" type="application/x-shockwave-flash" width="480" height="360" allowscriptaccess="always" allowfullscreen="true"></embed></object>

==Peer Review==

Group 6:
Nice introduction. The length is right. Perhaps what is missing is general image to make it less wordy.
History seems to be well researched but if you can make into a timeline would be great.
Nice layout in the Signs and symptoms Genetics/Aetiology. You may want to consider more images since the section are quite big. Also, add a description, copyright and reference for the images in the genetics and aetiology.
Well done in the table of diagnostic Tests. Do not forget to add the images.
In the Treatment and management, you may need to add some shading in the table because the lines of the table are not obvious and Prognosis needs more referencing.
In the future Directions, you may consider deleting the in text referencing. Finally, some of references need to re-format.

Well Done. --[[User:Z3284061|z3284061]] 11:53, 29 September 2011 (EST)

'''Group 6'''

* The intro needs some referencing
* An image might be good in the introduction
* Histroy section is good. A timeline might be helpful
* Epidemiology section needs more information
* Good table in Diagnostic Tests, however, images are missing
* An image would be good in either Prognosis or Future directions to break up the text
* Good flow to the project
* Good student drawn picture
* Glossary needs to be completed
* Double referencing needs to be fixed
--[[User:Z3292953|z3292953]] 11:08, 29 September 2011 (EST)

'''''Tetralogy of Fallot (Group 6) Peer Review:'''''

Introduction: Good content, however possibly revise grammar and structure of some sentences. Also, it would engage the reader more if they could visualize what you are saying through an image.

History: This section has the relevant information, however try using a different format to represent your ideas, such as a timeline or a table? Fallot image lacks a student template and images need to have the correct referencing format. Maybe too wordy for history? Try to make it a bit more succinct.

Epidemiology: Slightly short. Can you elaborate?

Signs and Symptoms: Good use of links to redirect the reader to more information. Image is good, however I think you could maybe put more images in this section to break up the text. Try revising some of the sentence structure. Otherwise, the information in this section is good.

Genetics/ Aetiology: This section is good, however some things need to be further explained. Example: “Gene affected = NKX2-5” – could you elaborate on this? Images are good and relevant.

Pathophysiology and Abnormalities: This section is impressive! Images are excellent and help the reader understand what you are describing in words. The fetal blood flow image lacks a student template. This section needs to be referenced.

Diagnostic tests: Obviously a lot of information here. I am sure I do not need to tell you that this section is incomplete. Images need to be added. I am slightly confused as to why there is a reference directly below the table? Couldn’t this be added to the reference list with the other references?

Treatment/ Management: This section is good. Image needs a student template, but otherwise well done.

Prognosis: Good information. However, surely you did not gather all of this information from the one reference? Also, maybe a picture would help to break up the information.

Future Directions: Good idea. This section is good.

Glossary: Could be expanded.

Overall, the page is coming along well. Nice work and good luck with the editing process! --[[User:Z3290808|z3290808]] 10:44, 29 September 2011 (EST)

Tetralogy of Fallot – Group 6

* Introduction is rather disjunct. No images here also. Also no referencing.
* History looks well detailed, however other groups have used a timeline or table to summarize this information. I think this would help it flow better and be more succinct.
* Epidemiology needs some work. No images and the text does not really explain the epidemiology well.
* Signs and symptoms looks well written, however maybe some more images here could be useful. Also a table might better summarize this information. The image used could be better explained also.
* Other sections look well structured and highly detailed. Looks like a lot of work and research has been put in. Images are well explained and correctly referenced.
* The future directions heading could also include some more detail current research projects as well as some comment on the overall direction that this future direction is taking.
* Glossary needs a lot of work to be complete.

--[[User:Z3288196|Z3288196]] 10:44, 29 September 2011 (EST)

'''Peer Review'''
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

Group 6:

Great intro, brief but covers everything. Good amount of references for the information provided
Genetics part was covered well.

The reference under diagnostic techniques should be with the other references and hopefully, by the end of semester there will be images where it says “insert images”

Good use of tables.

Maybe a few more pictures and the page will be perfect.

Evidently there’s been good work put in and the information has been researched well.

9-13 are all the one link so it should be one link not 5 separate links.

Clear and concise

z3332178 =]

'''Peer Review'''

*Introduction: the layout is a bit messy. Maybe get rid of the double spacing. It might also be a good idea to include an image e.g. maybe of a heart. Needs to include more references in this section.
*History section was well written. I suggest putting the quote in a blue box or highlighting it in some way to make it stand out. Try including a table or timeline to summarise the key events and findings.
*Signs and symptoms; Good layout and presentation of information. Easy to follow and understand.
*Genetics: shows it has been thoroughly researched. Like the use of images to compliment the text. Try and put the information in a table. The section is too lengthy in comparison with the other sections. Needs to hyperlink certain technical words to the glossary.
*Pathophysiology: well written. The information is concise and easy to understand. Good use of student drawn images.
*Great idea summarizing the information on 'diagnostic tests' in a table. Get rid of the in text referencing in the table.
*Add a border around the table in the treatment/management section.
*Other sections; good information. The referencing need to be fixed, it's not consistent. Try and include more images or tables in the prognosis, future directions sections to break up the heavy text. These sections seem a bit mundane compared with the rest. Prognosis section required more referencing.
*Glossary; need to be expanded.
--[[User:Z3291622|Z3291622]] 10:06, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*Introduction does not flow very well. Sentences are very choppy.

:*History section would benefit from a timeline rather than paragraphs as it is a bit hard to follow.

:*In the epidemiology and symptoms sections need some more content. Seems very minimal. Also images?

:*Diagnostic section needs the rest of the information added to its table. “Insert text here”. Also use of bolding or different font sizes would benefit this table.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:19, 29 September 2011 (EST)

Group 6 Peer Review

*Majority of page is in a logical and organised manner however maybe switch aetiology and signs and symptoms to make it flow better?
*History section had good, clear subheadings
*Epidemiology seems brief relative to other sections-perhaps merge with a section or expand on this if possible
*Table in Diagnostic tests-great however an image would help break up the text
*Glossary could be extended further
*Referencing inconsistent
*Image/text ratio is good however layout could be improved
*Overall, a very informative and interesting page. Visual appeal could be worked on but once a few things are adjusted, it will finish it nicely
--[[User:Z3308965|Fleur McGregor]] 09:10, 29 September 2011 (EST)

Group 6

*Introduction is good and very clear, except there are no references, easily fixed but (Y)
*History could be incorporated into a table, or at least, the dates could be bolded or highlighted to establish progress through time.
*Good use of subheadings under ‘Signs and Symptoms’, might be beneficial to include more images as examples of each symptom, but just enough to provide a balance between text and images
*Genetics – well organised information, incorporation of images is excellent, many of the terms mentioned here could be defined in the glossary
*’Pathophysiology and Abnormalities’ – this section definitely needs to be referenced, but good info.
*’Treatment/Management’ – this table needs borders, i was easily confused as to which paragraph i was reading, but great info.
*Glossary could have a lot more terms included.

--[[User:Z3331469|z3331469]] 07:02, 29 September 2011 (EST)

'''Group 6 Peer Review'''

• Nice and simple sub-heading structure. I like the consistency of two images throughout the page. However I feel like you have lots of text with fewer images.

• Introduction is clear and to the point, however where are you references? And an image in this section is always good to give a representation of the abnormality from the start.

• History is really good! Clearly researched very well and good images! Interesting to read. However, the use of a timeline or ‘bolding’ all the dates would make it an easier read.

• Epidemiology is good, however I think you could elaborate more and possibly add a table/graph.

• I personally think that your signs and symptoms would look better displayed in a table. Definitely need more images here, possibly one for each sign/symptom.

• Why are signs and symptoms before the aetiology and pathogenesis of the disease? For me, it’s more logical to explain the cause and how the disease comes about before the signs and symptoms.

• Pathophysiology and abnormalities is a really good descriptive section. Well explained! And good use of images. But where are all the references?

• Diagnostics test has interesting information. Inconsistent referencing system to the entire page, also desperately in need of images to break up all that text.

• Future directions is well summarised, with relevant headings.

• Not really sure what’s going on with your referencing, but you need to have a consistent system throughout the entire page with no doubling up of articles.

--[[User:Z3289829|z3289829]] 02:44, 29 September 2011 (EST)

*Intro: Best not to start off the introduction with stats, people will quickly lose interest. I like how you’ve given a very brief idea of each subheading. This section would benefit from a picture , something to grab your attention.

*History: A timeline would be best, as this section isn’t as significant as the others so it doesn’t need to be in extensive detail.

*Epidemiology: “ It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered” repetitive. Best if not mentioned in introduction, as it is useful fact in this segment. Needs a little more detail, quite short in comparison to other sections.

*Signs and Symptoms: Good use of subheadings, need more images. Loved the audio! Very interesting. This section needs to come in after aetiology though.

*Genetics/Aetiology: Quite extensive, very detailed and understandable, but a lot longer than the other sections, it could do with a bit of trimming. Also the one type of image being used 3 times is not appealing, perhaps hand draw it in different colours or get a different style of drawing representing it.

*Pathophysiology: Like the subheadings and it’s easy to follow the information.The first image is great, the 2nd image could be broken down and hand drawn to compare the normal blood flow with TOF blood flow individually, instead of having the other conditions included. This would make it more clear.

*Diagnostic Test: Table is clearly incomplete. Add images, and add colour. The text is also not referenced. Why is there one reference at the bottom of the table?

*Treatment: Quite detailed and informative. There are many sections missing references above the table.

*Glossary: INCOMPLETE. There’s many more words you can add here.

*References: Links to other pages don’t count as references- that needs to be fixed.

*Overall: Great job. You’re image:text ratio is little unbalanced, as you need more interesting pictures. Needs a few changes here and there as I’ve mentioned above but it’s looking good so far.

--[[User:Z3290270|z3290270]] 02:29, 29 September 2011 (EST)

'''Peer Review'''
* Introduction needs more/any references.
* Use of a quote in History is interesting.
* History sections seems to be too focused on certain specific procedures rather than their significance for the disease itself and the patients.
* Some grammatical errors in various sections.
* Epidemiology seems a bit short...if no other details can be found for it, consider merging it with another section?
* Signs and Symptoms can use more references, but the subheadings used are very fitting and set out the information well.
* The subheadings in Genetics/Aetiology mean nothing to me. Explanations? On that note, the glossary can be more filled out.
* The layout of Genetics/Aetiology can probably be tweaked a bit.
* Pathophysiology is set out very nicely, but it needs references.
* The table in Diagnostic Tests is very succinct, but the section needs some text, if only to introduce/explain the table. Also, there is a random reference at the bottom.
* Treatment/Management needs more references. The table therein is strange, but the information is very well presented.
* The inclusion of a Prognosis section is interesting, but maybe consider putting it within Treatment/Management?
* Inclusion of Future Directions is very good but the references need to be cleaned up.
--[[User:Z3290689|z3290689]] 01:15, 29 September 2011 (EST)

Group 6
*Introduction: well summarised, but paragraphs don’t flow. This section needs referencing and a few terms could be defined in the glossary.
*History: good use of images to break up text. Maybe consider a timeline just to summarise the section since there is a lot of information here to digest.
*Signs & Symtoms: I like the use of subheadings – clearly indicates topics discussed. Maybe consider un-bolding the list of mumurs since they are not headings, just to keep the formatting consistent.
*Genetics: I like the images which are consistent throughout and the use of gene profiles – nice touch.
*Pathophysiology and abnormalities: well written & formatted section. Referencing?
*Treatment/Management: The only thing I would suggest is to add borders to the table so that the rows are clearly separated. I like the external links.
*Perhaps the page needs just a few more images/tables to break up the heavy text. And the glossary should be expanded.

--[[User:Z3332327|Lisa Xiao]] 00:48, 29 September 2011 (EST)

Group 6
Hey, nice progress with your page, all sections have similar amount of content which were interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: Referencing needs to be improved here
#* History: content is good but too wordy. I think a summary or a simple timeline would be good
#* Epidemiology: Where's the reference for 3/10000 live births?
#* Signs: ok section, but could do with more images here
#* Genetics: If using abbreviations, such as TBX1 gene, you should explain what it is, ie. TBX1 gene (T-box 1). Also need to work on referencing here as well. How about organising all the content in a table? have in columns: gene, gene profile, frequency, etc.
#* Pathogenesis: I'm not quite sure about this, but do you need permission to adapt an image from an article? (I'm referring to the '4 defects' image)
#* Diagnosis: I'm sorry, but this section is a bit bland, though the content is very informative. I think some images here would be good
#* Treatment: Referencing! Also, personally, that green is too bright, maybe find a more neutral, soothing colour?
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to find more images, I feel some of the information could be more effectively presented in table formate rather than lengthy text
#Content is correctly cited and referenced.
#* VERY poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* research done is evident, just need to reference
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* glossary is very lacking in terminology
* need more images
* REFERENCING!

--[[User:Z3291643|z3291643]] 23:25, 28 September 2011 (EST)

'''GROUP 6:Tetralogy of Fallot'''
*Info in the intro is succinct and informative but sentence structuring and punctuation lets this down e.g. "These genetic mutations contribute to the four characteristic defects, in the heart of a patient having TOF" - comma is misplaced here
*"disease that occurs in 3 in every 10000 live births" -consider rephrasing this
*Intro needs an image to draw attention of reader
*While I appreciate the sectioning of the history section, i think that a chronological timeline may be more comprehensive for the reader, I feel that some of the dates are all over the place, also the history of this disease seams to stop at 1950s, could you maybe find more recent findings or contributions
*History images are good but need to be properly referenced and student template is missing from the first image
*I feel epidemiology section is a little underdeveloped, could you possibly find some more stats and compare incidence in several countries?
*Signs and symptoms has good info, but i feel that some sections could be expanded more
*signs and symptoms could use more images to accompany info
*I like the audio links to the heart signs
*Genetics/Aetiology section looks like it has been thoroughly researched, i like the structure of how each gene is dealt with, however, this info could be better formatted in a table and summarised a little more (if you are going to include all this technical info make sure it's explained in glossary maybe), also images in this section need better descriptions in the legends
*Pathophysiology and Abnormalities (I'm not sure if this is the best heading, could maybe be associated conditions or associated abnormalities or even just Cardiac abnormalities), info here is good but could be expanded a little more seeing as cardiac abnormalities seem to be a major manifestation of this anomaly
*Diagnostic tests section could be better placed further up? appears to have some info missing, and in some parts too much text, maybe could be summarised a little. Images could help break up the text, use of a table here is suitable but colour for the side headings could make it stand out a bit more. Referencing really needs to be fixed for this section
*Treatment and management is well researched, however Palliative Procedures could use more referencing esp. at the beginning. Table included is good but could be improved with colour and sectioning
*Prognosis has good inf but lacks referencing

Overall:
*More images are needed to balance out text
*Reference list needs work, don't think it's sufficient to just provide links to websites
*proof reading is needed to fix spelling mistakes, grammar issues and general sentence structure
*Glossary needs finishing, consider linking glossary words to the text and adding any acronyms used
*referencing of some images need to be fixed and student templates are missing in some

--[[User:Z3331556|z3331556]] 22:12, 28 September 2011 (EST)

'''Group 6'''

*The introduction is good but it would be better if there was some referencing.
*The history seemed abit chunky ? maybe a summarised version in a form of a timeline would be good. But overall the use of images is good, it breaks up the heavy text more.
*Epidemiology was abit too short, maybe expanding on why it is this pattern and etc would be a good idea.
*Signs and Symptoms had a nice summary of information. Maybe more pictures would make it more easy on the eyes because this section is quite big on the info. But the audio is a interesting idea!
*Genetics - Firstly, maybe get rid of mark's post. Secondly the layout of information is not that appealing, maybe you could underline the headings to make it more definite. Lastly, the use of images is good! it is very consistent for all genes.
*Diagnostic Tests section was not referenced! If it was then this section would be a winner, if it was completed!
*Overall, it looks like you guys have done alot of research. Good job!

--[[User:Z3330313|z3330313]] 00:01, 29 September 2011 (EST)

'''Group 6:'''

•Very text heavy, perhaps an image in the introduction could be added to grab the attention of the reader and create a better balance between text and images.

•Also, there are no references in the introduction. The source of this information needs to be references properly.

•The history section is worded well, though it may be more visually appealing and better formatted in a timeline. Also it seems to stop at the 1950s period. Is there no other recent research or developments made that could be added to bring the timeline up to date?

•The epidemiology section is quite short

•Good description of the signs and symptoms and good use of external links in this section for further information

•I like the diagnostic tests table, although it is incomplete at the moment, when the images and other information is added then this section will be very well done. Just make sure that it is referenced properly though, because it seems to be lacking referencing at the moment.

•Glossary needs to be completed and a number of the references are repeated

•Good work overall, some sections just need to be fixed up and completed and some more images added, but the overall formatting seems fine.

--[[User:Z3332183|z3332183]] 21:30, 28 September 2011 (EST)

'''Group 6'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there. History is well done, perhaps a time-line could be used?

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Good use of headings, subheadings in history was well used.

'''*Content is correctly cited and referenced.'''
File:Finger-Clubbing.jpg, File:TBX1.jpeg, File:NKX2-5.jpeg, File:JAG1.jpeg and File:Normal fetal blood flow and Tetralogy of Fallot.jpg should be referenced properly.

'''*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.'''
Well done student image with good explanation. More images would be good. Include more terms in glossary. Table in diagnostic tests has too much text. Table should be used to summarise, put main block of text outside of the table.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Prognosis needs more referencing.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Good information in genetics, but maybe relate the symptoms to problems? (eg: what does Conotruncal anomaly face syndrome mean for the person/fetus?)

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has developed wiki according to guidelines but some changes could be good.

--z3329495 21:18, 28 September 2011 (EST)

'''Peer Assessment Group 6-Tetralogy of Fallot'''

* An image in 'Introduction' will make the beginning of the page more lucrative
* History might work better as a timeline, with bullet points and bold the dates so it is easier to follow.
* Surgical history and Contemporary History has a lot of information, some of it overlaps.The whole section could be replaced by a 'easy to follow' timeline. Good pictures in history.
* Are you going to expand on 'Epidemiology',? Maybe talk more about the actual pattern of occurrence rather than just a couple of observations from epidemiological studies?
* Are you also adding a description for Aortic Insufficency Murmur? The other three heart murmur types have an explanation except for this one.
*There are too many gaps in between the lines, makes the page look a bit sparse.
* Genetics looks quite full on. You may want to add more distinct subheadings to make it easier to follow and keep the reader's attention
* 'Abnormalities' looks great however you might want to change the italics to just bolded headings, makes the page look more consistent. Also make the numbers bold if you are going to have the text following the number bold.
* Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Even though the table is coming along make sure you take the reference off from the bottom of the table and add pictures. It looks like a work in progress. Also the referencing style is different to the rest of the page
* The student drawn pictures under treatment is nice.
* The table is also quite succinct
* 'Future directions' doesn't sound great as a heading. Use something more appropriate to the context
--[[User:Z3308968|Tahmina Lata]] 19:21, 28 September 2011 (EST)

'''Peer Assessment Gr 6'''
*History – what has been done in the last 50yrs? It seems to stop around 1950.
*Signs and symptoms- needs to be edited so it flows better, avoid long wordy sentences – just break them up into 2 (e.g abnormal growth part). Do you have a pic of a blue baby?
*Genetics- need a bit more space between each gene section, just to make it really clear (e.g. between the end of 5q34 and 20p12.1)
*Diagnostic tests table is good (but incomplete), perhaps consider using colours like other groups has? But the bright green of the shunt table is too bright, it hurts my eyes haha.
*References under the reference table needs to be fixed – do you want them to be in the table, or a list of them or what? Same for the references in the future directions section.
*Very well researched and thorough explanations
*Maybe expand the glossary?
*Reference section has some that double up (one after another) – there is a way to fix this and condense it.
*Do you have some photos of real hearts that have been affected by this disorder?
--[[User:Z3332824|z3332824]] 17:46, 28 September 2011 (EST)

'''Group 6: Peer Assessment'''
* It would be good to see more images
* The introduction would be more engaging if it had an image
* The history section is informative however would be nicer in a chronologic fashion. May be a table?
* The extra surgical history makes it clear that surgery plays an important role. Good
* Signs and Symptoms and genetic abnormalities are good overall. Many of the terms need to be added to the glossary though and it might be better to put aetiology first.
* It's a quite big and text heavy table in your diagnostic section. May be you can make it shorter, put pictures in

* I found quite a few words that should be in the glossary
* There is no title for your reference section and it looks like you should have more references for the amount of text that you have written
* Overall your page is very informative, good content. You need more images, appropriate referencing and a more complex glossary. --z3279511 17:11, 28 September 2011 (EST)

'''Group 6 Peer Review'''
* Good introduction, although an image straight up would be nice!
* History is presented well, although a table format at the end that summarises everything you have said would be nice. Also, does the history stop around the 1950's? It seems like there has been nothing done on it until 1970/1980? Hence, the table format would be nice if it appears that I've missed information.
* Epidemiology section is really quite short. Is there nothing more that can be said on it? Does it have preference to specific race?
* Signs and symptoms - from the way that the page is formatted it appears that you've gone down onto the level 4 headings with 4 ='s paraphrasing each heading. Try to use 3 or so just to make sur e the headings are larger and each subsection can be identified.
* The genetics/aetiology section should be explained better; whilst this is aimed at academics, it is almost impossible to understand the information pertaining to the genetics section.
* The pathophysiology and abnormalities section is well explained, and the diagram is excellent to show exactly where the problem lies. A well done section, and a well-selected image for the blood flow patterns.
* Diagnostic tests: Still need to insert those images on the right hand side column! Also, ensure that the referencing is done in the correct format - this section still needs work.
* Treatment/Management section is done well, with a good balance between text and table.
* Current and Future research: Perhaps more dates? The formatting here also needs to be fixed up, and try to have dates on the papers that you are quoting from (although I understand it's difficult without the references in place)
* The glossary section needs more terms added to it! Especially from the genetics/aetiology section which is already terribly difficult to understand.
* Referencing section is quite short - but understandably the whole project feels like the referencing just needs to be finished.
* Overall a nice-looking project with a lot of promise. The spacing and format of the project makes it easy to read - perhaps more images and the use of some tables might also assist in the presentation of this project.
--[[User:Z3288827|Leonard Tiong]] 10:49, 28 September 2011 (EST)

'''Group 6'''

*My first impression is that this project is lacking images. There is way too much text in comparison to images.
*An image would nicely complement the introduction
*I feel that history would work better in a timeline
*Epidemiology needs a table/graph
*Good links in signs/symptoms although another image would be nice
*Genetics needs to be explained a little better
*Student drawn images were great- obviously a lot of effort has been put into these
*Diagnostic test table needs an image and needs to be referenced properly
*Again, an image is needed for prognosis
*Glossary needs to be extended
*Overall a good project but you need to fix a few things

'''Group 6'''

*Introduction: the contend is ok, but the structure could be clearer

*History: too text heavy, a timeline would be nice

*Epidemiology: more content would be good

*Symptoms: the picture could be more general

*Genetics/ Aetiology: the structure could be better, maybe use some more subheadings, and put the gene profile in tables

*Pathophysiology: you need references

*Diagnostic tests: why does it say “insert images”, that should be fixed

*Treatment/ management: looks like there are some references missing? Deleate “Want to learn about more surgery and treatment methods?”, the contend is good, types of shunt would look better as a table

*Prognosis: references missing? good use of subheadings,

*Glossary: incomplete
--[[User:Z3387190|Z3387190]] 21:52, 27 September 2011 (EST)

'''Group 6 peer assessment'''
*Introduction is clear though lack images where a image of example of a blue baby would suffice
*History begins clearly though becomes about surgical history instead of the disease, where time line is not even present of how understanding of this disease improved.
*Epidemiology should be expanded either the genetics of the disease, in general have more information of the causes, incidence and distribution of the disease.
*Signs and symptoms poorly structured and requires more images also doesn’t have an introduction to the signs and symptoms. Although the extra links to comparison of the heart is useful and nicely used.
*Pathophysiology should add supplementary information to back up all the information.
*Diagnosis please add the images, while there is the content though no image following also first box has “insert text” very confusing.
*Treatment/management indicate the separation of surgery and other treatment types in the introduction which is lacking otherwise all is A ok
*Glossary needs to be referenced to other sections of the web page also expanded as most language used is unknown without a dictionary.
*Referencing needs to be fixed as links is not proper referencing also the repeats need to be removed
z3332250 23:53, 26 September 2011 (EST)

===Comments on Group Project 6===
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

--Z3389806 08:03, 26 September 2011 (EST)

'''Group 6 Critique'''

#• Introduction is ok, however it needs to be structured a lot better than what it is
#• History is interesting
#• Epidemiology needs a lot more detail. A few lines is not good enough
#• Signs and Symptoms is ok
#• Genetics needs to be explained a lot more clearly than what it is
#• Abnormalities is ok
#• Diagnostic tests table is impressive
#• Treatment/management section is very good
#• Prognosis and future directions section is great
#• Glossary is incomplete. Check the first term and fix this

--[[User:Z3289991|Robert Klein]] 19:05, 24 September 2011 (EST)

'''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!

Group 6-
* No way near enough images. As I scrolled through there was HEAPS of text and only a few images, all of which are on the right hand side. It would be better if they were scattered around
* An image in the introduction would be helpful
* What are ‘tet spells’? mentioned in the introduction (described later but when seen in the introduction it looks like a typo)
* History would work better as a list of dates rather than paragraphs. I do like the section at the top with the quote though
* Epidemiology needs an image- perhaps a table or a graph.
* Signs and symptoms could do with another image to visualise the clinical manifestations
* I really liked the audio clips but the first one didn’t work on my computer? I couldn’t hear anything. Not sure if it was just me
* I think you can come up with a better way of formatting the genetics section. Maybe a table? The information is good it just looks a bit funny
* The pathogenesis doesn’t actually say HOW is happens in infants. Is this a condition formed during embryonic development or after?
* The diagnosis section is far from complete. This needs to be corrected
* Diagnosis section is also not referenced properly
* Why is there a reference at the bottom of the diagnosis section?
* As funny as this was: ‘Want to learn about more surgery and treatment methods? Check here!’…. maybe not appropriate sorry. It should be a little more formal. If you want the reader’s attention- try colour.
* Prognosis- image needed please. Maybe a graph?
* The glossary also needs to be extended
* The references need to be tidied up- there are also not many?
* You need to reference your images properly. ‘normal fetal blood flow and tetralogy of fallot’ is an example. You have but the copyright but not the reference. The web address is not a reference
* You are clearly on your way with the project but more work is required. You need to FINISH the content and format it a little better with more images.

''Group 6 Assessment'''
*First, I’d like to note good job on using a reference more than once in the correct way instead of referencing the same thing multiple times. At least this is done in the first few sections. First time I’ve seen this done correctly!
*The introduction, however, has no references whatsoever. Where did this information come from?
*It might also be good to add a simple picture in the introduction section so it looks more appealing.
*Good information included in the history section. It might look better if this were laid out in a bullet format though.
*The epidemiology section looks rather bland. Not only is there not a picture, but there also isn’t very much information included. Think about what else you could include here or what you could go into depth about.
*The signs and symptoms section has good information, but it might be a good idea to represent this information in a better format, possibly in a chart, with pictures of each symptom included in the chart.
*Finger-clubbing.jpg also needs a detailed description still.
*Good organization and format under the Genetics section.
*Under the pathyphysiology and Abnormalities section there are no references made. Where did this information come from? Diagnostic Tests and Treatment also needs more referencing.
*Pictures still haven’t been inserted into the Diagnostic Tests chart.
*More referencing is needed for the Prognosis section. Also, does the glossary terms need to be referenced?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. References 7-14 are the same reference. Fix these so they are under one single reference number.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Overall, there is a substantial amount of information given within this page, which is good. I like the basic format of everything and most of the pictures which are included. Just work on weaving everything together better and referencing things correctly. Good job!

--[[User:Z3391078|Z3391078]] 15:32, 27 September 2011 (EST)

'''Group 6'''
* Nice overall structure and good use of headings and subheading. It gives the page a nice flow.
* INtroduction is nice and straight to the point and gives the reader a good overview of your topic.
* I like the historical section with interesting subheadings used, maybe you could add a timeline just to simplify the info.
* Signs and symptoms nicely arranged. could you add some more pictures here?
* Pathophysiology and Abnormalities section need to have the references accompanying the information. Just so the read can identify where all the info is from.
* The diagnostic tests table would be nice with some colour and when the images are it will look complete. It's a little text heavy for a table maybe try bullet points. also the referencing system has changed in this table? and a little unsure of the reference at the bottom of the section?
* Treatment/Management section is nicely arranged.. could you add another picture here just to compensate for the amount of text. the table really brightens up the page!
* Future directions section is nicely summarised and I like the tone of voice used here. just make sure the referencing is correct as it is a little confusing and interrupts the flow of the section.
* Maybe the use of similar tables and colour scheme will increase the continuity of the page.
* Make sure your references are not doubled in the list.
* Ensure all of your pictures are correctly referenced.
* Make sure all acronyms and scientific wording is in the glossary.

*'''Intro''': What's a tet spell?
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.
*'''Edidemiology''': Looks fine
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.
*'''Glossary''': A bit poor. More technical terms need to be explained.
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!

'''Peer Assessment: Group Project 6'''
*The introduction and the section on pathophysiology and abnormalities have no references. This needs to be rectified.
*The introduction and some of the history section have short paragraphs that are only one sentence long and would be improved, both for formatting and information purposes, by incorporating them into the rest of the information.
*Inserting a small timeline in the history section would make the sequence of events more accessible to the reader.
*Some sentences are too long such as, 'Children with TOF don’t grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth'. This sentence could be broken up and also improved by a greater explanation of why the process of growth is abnormal in TOF.
*Maybe explain more about what 'clubbing' is.
*In the diagnostic tests section the images need to be inserted and needs to be properly referenced. The information is good but as noted one section is totally void of text.
*The section on prognoses needs proper referencing.
*The section on future directions is well written, however the referencing needs to be adapted to the wiki format.
*Under the information in some of the images you have uploaded such as in the portait of A. Fallot, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*The project is informative, however formatting and referencing are issues that need to be addressed.
--[[User:Z3217345|z3217345]] 22:23, 27 September 2011 (EST)

'''Group 6:'''
* Introduction: Maybe briefly explain the symptoms and the physiological implications of a tet spell and what palliative care is, alternatively hyperlink these words to the signs and symptoms and treatment sections. There are also a few mistakes such as no space after commas “chromosomes 5,20 and 25.” and an incorrect capital letter after a comma “TOF patients include, Infants turning blue”, just make sure to correct these little mistakes by re-reading this section. An image here would also be good.
*History: The history you do have is very comprehensive and easy to read, however the dates get lost in amongst the text. If you bold the dates or include a brief table after the text it will help the reader to track the history better.
*Epidemiology: Very short, could you maybe elaborate to why TOF affects slightly more males than females?
* Signs and symptoms; the information here is very good, it could be improved with the use of more images. I’m not sure if it’s just me or not but I couldn’t hear anything in the normal heart video but the TOF heart video was fine?
* Genetics: This section genuinely scared me, it is a lot of text and a lot of scientific text at that. I found it difficult to read and ended up skipping over this section. Maybe try explaining the genes in your own words. The images do help though so maybe make them bigger. I did find a little typo “gene taht results to TOF” so make sure you proof read once you’ve edited again.
* Pathophysiology and abnormalities is done really well with great visual aids (second image needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>). Only suggestion is to leave the sub-headings just bold - no need for italics.
* Diagnosis is obviously unfinished but once the images have been added, the blank text has been filled and some colour is added to the table, I think it will be a great section.
* Treatment and management: The image here is also missing the student template. Spelling mistakes found so proof reading is required “oxygen & intravenous morphine to provides more blood flow”. The table here could be coloured to liven up the page.
* Prognosis is done well but maybe a pie graph could be inserted to show the major causes of death in surgically untreated patients as a visual.
* Future directions is also very good – the referencing just needs to be fixed.

--z3290815 20:31, 28 September 2011 (EST)

'''Peer Review'''

* really well done
* format and structure of the wikipage was consistent throughout

--[[User:Z3060621|z3060621]] 21:36, 28 September 2011 (EST)

Test:

{| style="color:black; background-color:#ffffcc;" width="85%" cellpadding="10%" cellpadding="15%" cellspacing="0" border="1"
| colspan="2" | '''Diagnosis'''
|}

--[[User:Z3291423|z3291423]] 11:57, 22 September 2011 (EST)

Hey Jaz, thanks for letting me know...my english can fail me at times.....lol...fixed it up... regards--[[User:Z3291317|Z3291317]] 18:49, 18 September 2011 (EST)

Hey guys! i just realised that the caption of helen taussig and ballot say portraight....not PORTRAIT!?!! i tried to change it but it don't really know how..anyone have any ideas to this?! :S thanks --[[User:Z3291423|z3291423]] 00:06, 17 September 2011 (EST)

Table Test! --[[User:Z3291423|z3291423]] 22:16, 16 September 2011 (EST)
{|
|-bgcolor="# 99FFFF"
| '''Type of Shunt'''
| '''Description'''
| '''Reasons for it not being used'''
| '''Image'''
|-
| Pott’s Shunt
| This shunt is a connection that is established between the lower part of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery.
| The shunt has a tendency to increase the pulmonary blood flow and it is also very hard to close when complete repair is undertaken
| Insert image
|-
| Waterston Shunt
| This shunt was placed between the back of the Aorta, to the right branch of the pulmonary.
| This shunt’s use is more suited to those with pulmonary artery stenosis and also the procedure is quite difficult to perform.
| Insert Image
|-
| Glenn Shunt
| The Super Vena Cava is anastomosed via a shunt to the right pulmonary artery.
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task.
| Insert image
|}

Table test (fingers crossed!) --[[User:Z3291324|Jacqueline Ellero]] 10:49, 15 September 2011 (EST)

==TOF diagnostic techniques==

{|border="1px" cellspacing="1" align="center" cellpadding="5" style="background:seashell"

|+ This table describes different diagnostic tests for TOF
! Diagnostic technique !! How the procedure works !! Presentation in TOF patient !! Image

|-
|Physical examination
|TOF is often diagnosed during fetal life by echocardiography (Apitz, Webb, & Redington, 2009). If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation. These signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with cyanosis and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. (Somerville, 1993)

|Insert text here
|Insert physical examination image
|-
|Heart murmurs
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions.
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh systolic ejection murmur may be heard and a palpable thrill may be felt along the left sternal border. These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). http://ccjm.org/content/77/11/821.full
|Insert heart murmur image
|-
|Electrocardiogram
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device.
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.(Somerville, 1993)
|Insert electrocardiogram image here
|-
|Chest radiograph
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnoses many conditions including the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. (Bailliard & Anderson, 2009) The radiograph will also show a right-sided aorta in approximately one-quarter of patients. (Somerville, 1993)
|Insert CXR image here
|-
|Echocardiogram
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. (Bailliard & Anderson, 2009)
|Insert echo image here
|-
|Magnetic resonance imaging
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray.
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect. (Somerville, 1993)
|Insert MRI image here
|-
|}

Hey peeps just put a intro just as a draft...tell me what you guys think of it. Edit it as you may wish.... And Jaq, if you describe briefly how each test works it would be good, regards --[[User:Z3291317|Z3291317]] 23:16, 14 September 2011 (EST)

hey jaz, ive fixed up the diagnosis, but feel free to add anything! or let me know if you think i should add anything. --[[User:Z3291324|z3291324]] 10:06, 14 September 2011 (EST) should i describe each diagnostic test!!??--[[User:Z3291324|z3291324]] 10:07, 14 September 2011 (EST)

Hey Guys! just added a very few changes, links etc to treatment. I've begun to add make a bit of notes on diagnosis that could just add a bit of detail to the diagnosis section. just wondered if any of you guys know what particular section of the ECG indicates...Left Ventricular Hypertrophy etc maybe ill call up a cardiologist :P nonetheless ill add references and some things to diagnosis tmrw night. regards, --[[User:Z3291423|z3291423]] 00:15, 14 September 2011 (EST)

Hey jaq. no particular order, the referencing system in the wiki automatically arranges it according to the order it is found in the text. In text referencing is NEEDED, lol. Type in the text title into Pubmed and when the article is found, the pmid code will be found at the bottom of the abstract for that article. if you cant figure out how to reference, put in the pubmed ids as intext citations then ill fix it for you...Make pathophys a bit more simpler, but do not compromise the anatomical words, i.e. write the anatomical word, then write in brackets what it means, eg. ''...anterolaterally (at the top away from the midline)'' is just an example (a crap one to lol). Also did you find any new info for diagnostic tests? and Rom, why did you remove info from the 22q section???? regards --[[User:Z3291317|Z3291317]] 22:02, 13 September 2011 (EST)

hey guys, quick question about the referencing. are they in any particular order? or should i just add mine to the end of the list? and do we need to do in-text referencing?? and how do you find the pmid code? also, any suggestions on how i should improve pathophys? ie make it more anatomical based or reword it so its simpler? thanks --[[User:Z3291324|z3291324]] 21:30, 13 September 2011 (EST)

Hey Rom, looking good thus far. if you need help with referencing even after trying so much i can help you during the 1 hour we have afta the lecture tomorrow to go through and help you fix em up... its a bit tricky but can get a handle of it... --[[User:Z3291317|Z3291317]] 20:37, 12 September 2011 (EST)

Hey guys sorry for the delay, but I'm slowly uploading all my stuff up. I'm just a bit confused about how I do the reference tag thing, as you can see there is a massive red thing on our reference list. I tried copying how you guys did it but I failed at it. I'll be posting some more in the next couple of hours, I just need to get a hang of this coding thing gah!
--[[User:Z3290841|z3290841]] 19:36, 12 September 2011 (EST)

hey rommel, we really need to see your part of the project and get your suggestions on parts we have done because its due on thursday --[[User:Z3291324|z3291324]] 19:16, 12 September 2011 (EST)

Hey Peeps, Just reconstucted the referencing so they are done exactly as it should be... Also just uploaded a pic of Mr fallot Himself without any copyright restrictions ( aha ow ye ow ye, took me long before i found it lol). I left the intext references jac and jaz put in their sections for future reference. Thats about it for now... Jaz i hope u liked the pics i showed you, and i hope rom is going well in his section... See yous soon... Regards --[[User:Z3291317|Z3291317]] 17:36, 11 September 2011 (EST)

update: uploaded the drawn images, took ages but its finally done :) and I've just finished the future directions :) so it should be fine to edit and look over in the next couple of days!
regards --[[User:Z3291423|z3291423]] 13:16, 11 September 2011 (EST)

looking good jaz. thanks for the articles fru. ive had a quick look at them but will need to fix it up after work this arvo! --[[User:Z3291324|z3291324]] 11:59, 11 September 2011 (EST)

Hey Jac, ive got 2 articles that i will send to your email, both talk about Cardiac Magnetic Resonance, one some detail about electrocardiography. Also, Jaz i have an article that has a section based on 'Future Innovations' for TOF, have a read and i reckon it will help out with the future directions part... i will send these articles to your emails so look at them when yous can... and rom, you breathing my friend?... regards --[[User:Z3291317|Z3291317]] 01:29, 11 September 2011 (EST)

hey guys, just reworded diagnosis so it makes sense. can anyone suggest any good articles to read for diagnosis? im having trouble accessing a lot of articles (they keep asking for passwords) and a lot of the articles dont discuss diagnosis in much detail at all. help is much appreciated!! thanks :) --[[User:Z3291324|z3291324]] 21:12, 10 September 2011 (EST)

hey rom, this might be helpful for genetics. not sure what youve got already though http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747103/
--[[User:Z3291324|z3291324]] 20:50, 10 September 2011 (EST)

also what should i do about the symptoms-pathophys overlap. should i alter the pathophys so its more anatomical like in the below article??--[[User:Z3291324|z3291324]] 20:10, 10 September 2011 (EST)

On to it now fru. thanks for the article. should i reword pathophys too so its easier to read/understand?--[[User:Z3291324|z3291324]] 20:08, 10 September 2011 (EST)

Hey Fru: in regards to the below comments, im working on future directions now :) also i read through the history section and it seems a lot more better :) just one mistake is the
"durng such operations there need". Ill have my edited prognosis and futures up by tonight! :) ohh and the heart! regards --[[User:Z3291423|z3291423]] 11:03, 10 September 2011 (EST)

Hey Jac i was reading the article: Review - Tetralogy of Fallot by Frederique Bailliard and Robert H Anderson ( im sure you have this one) and theres a section absed on " Anatomical variants of Tetralogy of Fallot, and associated anomalies". i believe if you could also include this section into the Pathophysiology section it would be great! Furthermore would you please do the things Mark said in regards to your sections it would be good, especially the diagnostic tests part :). Also to everyone we need to get Future Directions and especially Genetics up ASAP! thus respective people have them completed asap. --[[User:Z3291317|Z3291317]] 22:49, 9 September 2011 (EST)

Hey jaz, the prognosis sounds pretty good. maybe expand/explain how the hypoxic spells, brain abscesses etc cause death. i think in general we could expand upon most sections. off to work now guys but ill fix up my couple of sections tonight/tomorrow morn! --[[User:Z3291324|z3291324]] 08:30, 9 September 2011 (EST)

Thanks Fru! I will definitely crack onto those suggestions, I'm going to first email the owner of the children's hospital video on youtube to get permission for using the video, and then ill put it up in my section.
ALSO, I've nearly done the picture! I've got an outline and as your reading this, i should have it coloured, labelled and ready for upload! :D

have a great weekend guys!

Reagards
--[[User:Z3291423|z3291423]] 23:29, 8 September 2011 (EST)

Hey jaz just read your prognosis section. You made it well, however,i picked up 2 things you could do and it woould be good if you do them: 1. The causes of death after no surgery has done; if you can explain how these 'causes of death' occur due to TOF, it will portray the role TOF has in these problems. 2. You should talk about any complications that could arise in both patients that dont have corrected TOF and the ones who do have the surgery (i.e. any conditions that could develop after having the surgery or not, not just the death of the patient if they dont correct their heart). Other than that great work! :) --[[User:Z3291317|Z3291317]] 23:17, 8 September 2011 (EST)

Ye Jaz, thanks for the pic. Aswell ive attached a reviewed file of the treatment section on an email i sent to you. Maybe the youtube cideo based on the TOF fix up can now be put under this section as an embedded video... --[[User:Z3291317|Z3291317]] 22:19, 8 September 2011 (EST)

hey jaz, the treatment section is much better, much easier to read. thanks for the heart pic! im pretty sure my section is he one that is too "verbose" so anyone feel free to fix it up--[[User:Z3291324|z3291324]] 19:47, 8 September 2011 (EST)

Hey Guys! sorry prognosis took me a bit longer to do, but It will be up by tonight :) and ill upload the heart pic as well :) which took forever to make!
regards --[[User:Z3291423|z3291423]] 16:05, 8 September 2011 (EST)

hey guys just put up some diagnosis, let me know if you want me to add anything to it. furkan, glossary looks good! rommel, how are you going with the genetics do you need any help? and jaz are you able to post up the prognosis? once they are all up we should go through and edit them all together and fix up the wording. --[[User:Z3291324|z3291324]] 15:50, 8 September 2011 (EST)

Hey peoples...im going to start constucting the glossary wordbank as i read the entire document. Please add words yous think i missed out on... Also i found a pic of Mr Fallot but i think theres copyright rights on it. i think i gotta clear it somehow...--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

hey jaz, i think the treamtment section is alright. maybe reword the first bit into sentences (i think it was the bit on how severe the cyanosis is) so its a bit clearer. but otherwise good :) what do you think about pathophys?--[[User:Z3291324|z3291324]] 12:40, 7 September 2011 (EST)

hey guys, i cant tell if this pic has copyright or not. can someone please have a look for me? http://www.nhlbi.nih.gov/health/health-topics/topics/tof/ thanks!--[[User:Z3291324|z3291324]] 09:49, 6 September 2011 (EST)
--> REPLY: I looked at the pic and looks great. however, i couldnt see if it was copyright or not. HOWEVER, it is found on a public government website, and from what i remember Mark said we can use these materials. To make sure just please check it with him aswell. Also, im going to format your pathophysioligy section now so it looks prettier :)--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

Hey guys, i Just finished the Treatment part, I've got palliative in this heading to still complete but Its very brief so i thought id get cracking on getting that drawing done and also the prognosis will be up by tomorrow! also check this out! http://www.nemours.org/content/dam/nemours/www/filebox/service/medical/cardiology/defect/tof.swf
--[[User:Z3291423|z3291423]] 23:57, 5 September 2011 (EST)
-->REPLY: Cool animation. Would we use an external link to this animation due to copyright restrictions?--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

Hey Peepz

I just finished the sections of History, Signs and symptoms and Epidemiology

just please check these sections, especially the epidemiology one, do yous want it more detailed or is it enough?

z3291324 your section seems alright so far, show us your edited version so we can fully critic it then.

p.s. the post below my one i dont really understand itl who is speking to who and what are yous refering to? lol

Regards --[[User:Z3291317|Z3291317]] 23:44, 4 September 2011 (EST)

j: the article on future treatment directions sounds good. i might add some of the info in to the pathophysiology section because it links in well with the pulmonary stenosis and right ventricular hypertrophy. --[[User:Z3291324|z3291324]] 13:47, 2 September 2011 (EST)
I think this article makes some good points which could be added into the treatment section (eg discuss treatment/surgery after birth and also follow up treatments in adulthood- pulmonary valve replacement etc due to valvular incompetence and regurgitation because of the growing heart)

=pathophysiology=
hey guys. ive written some basic notes (UNEDITED) for pathophysiology. Just want to get an idea of how much detail i should go into before i start adding links to journal articles etc. can someone please have a quick look through and give me an idea of how much more detail is needed. thanks :)

The four features of tetralogy of fallot are pulmonary stenosis, overriding aorta, ventricular spetal defect and right ventricular hypertrophy. These features result from the anterosuperior displacement of the infundibular septum. The severity of symtpoms is determined by the extent of right ventricular outflow obstruction. 
'''Pulmonary stenosis'''
(Symptoms include cyanosis, right ventricular hypertrophy, hepatomegaly and peripheral oedema (of the legs). More mild symptoms include sudden fainting and dizziness from exercise. ) 
Valvular or infundibular stenosis (narrowing of the outflow tract of the right ventricle). Obstructs the outflow of blood from the right ventricle reducing pulmonary flow. If the pulmonary stenosis is mild, a left to right shunt (with no cyanosis) will form, due to the higher pressure in the left ventricle. However, significant pulmonary stenosis can raise right ventricular pressure above the left ventricular pressure and cause a right to left shunt (cyanosis etc). The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. 
'''Overriding aorta'''
The aortic valve has a biventricular connection. Instead of being positioned over the left ventricle, the aortic valve is located above the interventricular spetal defect allowing blood from both the right and left ventricles to pass through the aortic valve. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. Because the right ventricle receieves deoxygenated blood from the systemic circulation, the percent oxygenation of bloood entering the aorta and hence back into the systemic circulation is decreased. 
'''Ventricular septal defect'''
The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. During ventricular contraction, blood from the left ventricle passes into the right ventricle and then re-enters the pulmonary circulation. Leakage of blood from the left to right ventricle raises the right ventricular volume and pressure resulting in pulmonary hypertension. (Shortness of breath, dizziness and fainting) If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience cyanosis and deoxygenated blood is by-passing the lungs and entring the systemic circulation. (also breathlessness, poor feeding and failure to thrive in infancy.) 
'''Rigth ventricular hypertrophy'''
Compensatory response to pulmonary stenosis ...to be contined.

--[[User:Z3291324|z3291324]] 13:38, 2 September 2011 (EST)

=link to pathology textbook=

hey guys, this is the link to tetralogy of fallot in robbins pathology
--[[User:Z3291324|z3291324]] 13:05, 2 September 2011 (EST)

=More genetics and Surgery=

Hey Peeps, i forund another article in regards to Genetics as it does an genotype-phenotype anaylis os TOF Patients. Have a read and see if it can help in the assignment subsection. if you cant get the full article tell me and ill give you the pdf of it.

Article: PMID: 19948535

And Regards to surgery and its prognosis post-operation i found these articles that may be helpful for 3291423. Again if yous cant find the pdf tell me and i'll send yous the pdf articles of these.

Articles: PMID: 20091166 ; PMID: 21769263 ; PMID: 21566339 (hey 3291423 this is the article i showed you in the lab and you wanted it from me)

Anyways peeps i hope all the assignments are coming along well

Regards --[[User:Z3291317|Z3291317]] 19:03, 1 September 2011 (EST)

REPLY: Thanks z3291317, I had a look through the files and am using them now for summarising :) also, can you send through the picture of what you want the abnormal TOF heart to look like and ill get cracking on it to produce/draw it :)

regards --[[User:Z3291423|z3291423]] 22:15, 1 September 2011 (EST)

=Genetics=
Hey guys, found some articles relating to genetics and the deletion of the 22q11 gene. take a look :)
--[[User:Z3291423|z3291423]] 21:09, 27 August 2011 (EST)

AS Bassett, EWC Chow and J Husted et al., Clinical features of 78 adults with 22q11 deletion syndrome, Am J Med Genet 138 (2005), pp. 307–313. http://pediatrics.aappublications.org.wwwproxy0.library.unsw.edu.au/content/112/1/101

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science?_ob=MiamiImageURL&_imagekey=B6T18-3V8RDDJ-11-1&_cdi=4884&_user=37161&_pii=S0735109798002599&_check=y&_origin=&_coverDate=08%2F31%2F1998&view=c&wchp=dGLbVlW-zSkWz&md5=0a4f32c3b75ebff2513309081ac0468f&ie=/sdarticle.pdf

http://pediatrics.aappublications.org.wwwproxy0.library.unsw.edu.au/content/112/1/101

=Treatment and future directions info/readings=

Hey guys, found this really amazing article about treatments and their repercussions http://www.ccjm.org/content/77/11/821.long#abstract-3
--[[User:Z3291423|z3291423]] 21:09, 27 August 2011 (EST)

=Online lab 4 info=
I my friends , colleagues and countrymen am going to be undertaking the research of the subsection Genetics/Aetiology in the topics that have been discussed. --[[User:Z3290841|z3290841]] 10:18, 25 August 2011 (EST)

Im going to be researching Treatment/Management, Prognosis & Future directions. - z3291423

regards, --[[User:Z3291423|z3291423]] 23:30, 24 August 2011 (EST)

Thanks for typing them up. I'm going to research Pathophysiology and abnormalities and diagnostic tests.
--[[User:Z3291324|z3291324]] 15:40, 24 August 2011 (EST)

Hey Group 6

From the Meeting on Tuesday after the Embryo lecture, we had concluded that we are going to divide the group project of TOF into the following sub-sections (if i am not mistaken):

* Introduction
* History
* Epidemiology
* Signs and Symptoms
* Genetics/Aetiology
* Pathopgysiology and Abnormalities
* Diagnostic Tests
* Treatment/Management
* Prognosis
* Future Directions
* Glossary
* References

From these subsections, I (z3291317) will research the History, Epidemiology and Signs & Symptoms subsections of the group Project.

Just wanted to put forward my part for the group project :)

Regards --[[User:Z3291317|Z3291317]] 15:01, 24 August 2011 (EST)

=Resources=
Hey Group 6

When i was looking around for info in regards to TOF, i found some videos on youtube made by an american hospital which we could use on our page in the "more info" section. Check them out and tell me what yous think...

- http://www.youtube.com/watch?v=ACRfFkxow7w
- http://www.youtube.com/watch?v=jgLC2QABcxo

So what you guys think? --[[User:Z3291317|Z3291317]] 22:54, 21 August 2011 (EST)

COMMENT: great stuff! that really is a great tool, maybe we can incorporate that in as a link, or something to really explain it! without all the mumbo jumbo :) --[[User:Z3291423|z3291423]] 22:22, 22 August 2011 (EST)

=Articles=

Found really good article detailing some clinical aspects http://journals.cambridge.org.wwwproxy0.library.unsw.edu.au/action/displayAbstract?fromPage=online&aid=331031 its called: The clinical anatomy of tetralogy of Fallot, http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0140673609606577 - Tetraology of ballot by christian apitz, just google scholar it via unsw or use the link I've given you :) --[[User:Z3291423|z3291423]] 19:10, 20 August 2011 (EST)

=Images=
Hey guys, this is an image of tetralogy of fallot with pulmonary atresia

[[File: Tetralogy of Fallot with pulmonary atresia.jpg]]
--[[User:Z3291324|z3291324]] 22:07, 17 August 2011 (EST)

Hey guys, just found this still frame showing large ventricular septal defect, aortic override, and right ventricular hypertrophy which are all very common to patients with ToF
[[File:Some common effects for patients with Tetralogy of Fallot.jpg]]
--[[User:Z3291423|z3291423]] 21:43, 17 August 2011 (EST)

Hey guys this is my image of our disease, it is just outlining some of the basic changes that happens to the heart, mainly the right ventricle.

[[File:Right ventricle of heart with Tetralogy of Fallot.jpg]]

--[[User:Z3290841|z3290841]] 13:42, 17 August 2011 (EST)

----

Hey Group 6, its z3291317

I just wanted to make it clear that we add all new entries into our discussion page at the top of the page and not at the bottom of it. Thats how we are told to edit this discussion page.

Anyways this is my Image for Lab 3 Question 2:

[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg]]

I hope it would be beneficial for our page...

--[[User:Z3291317|Z3291317]] 12:05, 17 August 2011 (EST)

--[[User:Z3291317|Z3291317]] 17:00, 7 August 2011 (EST)
Hey Group 6

i just done some research on a possible group project subject. It is quite detailed and interesting (to me) disease to write on.What do you guys think? Here is the review and research article for it:

The Disease:'''Tetralogy of Fallot'''

Review Article:

Orphanet J Rare Dis. 2009 Jan 13;4:2.

'''''Tetralogy of Fallot.'''''

Bailliard F, Anderson RH.

North Carolina Children's Heart Center, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. frederique_bailliard@med.unc.edu

Link: <ref><pubmed>19144126</pubmed></ref>

Description: This paper gives an overview about the disease, how it happens, and clinical manifestations.

Research Article:

J Med Genet. 2010 May;47(5):321-31. Epub 2009 Nov 30.

'''''Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.'''''

Rauch R, Hofbeck M, Zweier C, Koch A, Zink S, Trautmann U, Hoyer J, Kaulitz R, Singer H, Rauch A.

Institute of Medical Genetics, Schorenstrasse 16, CH-8603 Zurich-Schwerzenbach, Switzerland. anita.rauch@medgen.uzh.ch

Link: <ref><pubmed>19948535</pubmed></ref>

Description: A study was done to see the prevalent phenotype for Tetralogy of fallot, and it was found that the 22q11.2 deletion was the most common type in Tetralogy of Fallot.

'''''References:'''''

<references/>

--[[User:Z3291317|Z3291317]] 17:00, 7 August 2011 (EST)

----

--[[User:Z3290841|z3290841]] 09:36, 8 August 2011 (EST)

Hey Guys,

I did research on Cystic fibrosis and these are the 2 articles that I found that explains a lot about the disease, and the genetic research on it.

Review Article:

'''Cystic Fibrosis: Seminar'''

Description: This is basically outlining the pathophysiology of the disease, disease manifestation,current treatments diagnostic tool.

Ratjen F & Doring G.(2003).Cystic Fibrosis: Seminar.''The Lancet'', 361, 681-9. Retrieved from http://www.sciencedirect.com/science/article/pii/S0140673603125676

Research Article:

'''Gene expression profile study in CFTR mutated bronchial cell lines'''

Description: This article provides information about the severity of gene expression in relation of the extent or type of mutation.

Gambardella S, Biancolella M, D'Apice M, Amati F, Sangiuolo F, Farcomenti A, Chillemi G, Bueno S, Desideri A & Novelli G.(2006).Gene expression profile study in CFTR mutated bronchial cell lines.''Clinical and Experimental Medicine '', 6, 157-65. Retrieved from http://proquest.umi.com/pqdlink?Ver=1&Exp=08-05-2016&FMT=7&DID=1187181501&RQT=309&cfc=1

--[[User:Z3290841|z3290841]] 09:36, 8 August 2011 (EST)

--[[User:Z3291324|z3291324]] 20:48, 10 August 2011 (EST)

Hey guys, I like the disease that Furkan found (tetralogy of fallot)! What does everyone think?

These are the two articles I found. The review article gives a pretty good description of the disease, symptoms, treatment and complications etc. The research article looks at some of the genetic causes.

Goldmuntz, E., Geiger, E., & Benson, D. W. (2001). NKX2.5 mutations in patients with tetralogy of fallot. Circulation, 104(21), 2565-2568.

Apitz, C., Webb, G. D., & Redington, A. N. (2009). Tetralogy of Fallot. Lancet, 374(9699), 1462-1471.

Hey kiddes just done some research! check it out, its about Hypoplastic left heart syndrome

Review article:

2001 May-Jun;21(3):705-17.
'''Hypoplastic left heart syndrome.'''
Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP.

Link: [http://www.ncbi.nlm.nih.gov/pubmed/11353117]

Research:

2011 Aug 1;108(3):421-7. Epub 2011 May 31.
'''Prenatal diagnosis of hypoplastic left heart syndrome in current era.'''
Kipps AK, Feuille C, Azakie A, Hoffman JI, Tabbutt S, Brook MM, Moon-Grady AJ.
Link: [http://www.ncbi.nlm.nih.gov/pubmed/21624547]

References
<references/>
1. Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP ""Hypoplastic left heart syndrome.""Radiographics. 2001 May-Jun;21(3):705-17 <ref><pubmed>11353117</pubmed></ref>

2. Kipps AK, Feuille C, Azakie A, Hoffman JI, Tabbutt S, Brook MM, Moon-Grady AJ ""Prenatal diagnosis of hypoplastic left heart syndrome in current era."" Am J Cardiol. 2011 Aug 1;108(3):421-7. Epub 2011 May 31 <ref><pubmed>21624547</pubmed></ref>

==Peer Assessments==
* I would suggest placing the history section into a timeline or table format just so that significant dates are more clear and emphasised.
* The gene profile section was great. It was in detail, it was coherent and the inclusion of gene images enhanced my understanding of this particular section.
* Maybe for the “how the procedure works” section of the diagnostics table could have been summarised into a flow diagram or through images, rather than having a chunk of text. This could make it more straight forward to the reader.
* Your website was generally well-written and to the point. You varied your formatting regularly which made your page entertaining.
* My last suggestion would to only use the image of the shunt once and finding a different image as the repetitiveness of this is slightly disengaging
--[[User:Z3332629|z3332629]] 15:26, 22 September 2011 (EST)

2011 Group Project 6

2011-10-12T11:57:50Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of Tetralogy of Fallot (TOF) is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for T-box 1 transcription factor (TBX1). As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a microdeletion of 3 or 1.5 Mb of 22q11.2 region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a haploinsufficient gene. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a 30-bp duplication in exon 9c, a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is dose-dependent, which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the NK2 homeobox 5 transcription factor (NKX2-5 protein). NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene Jagged-1 protein (JAG1 protein), which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a missesnse mutation of the JAG1 gene identified at the 821st base pair. This is a G to A substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute [[#Glossary | '''cyanosis''']] usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] [[#Glossary | '''morphine''']] provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*[[#Glossary | '''Asymptomatic''']] patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a palliative method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the hypertrophy of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) [Xu H, Baldini A (2007) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made surgically between adjacent blood vessels.

'''Annular hypoplasia''' – (need definition)

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Asymptomatic''' - producing or showing no symptoms.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - Blood returning to the heart is diverted through a heart-lung machine (a pump-oxygenator) before returning it to the arterial circulation. The machine does the work both of the heart (pump blood) and the lungs (supply oxygen to red blood cells).

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - existing or taking place, within veins.

'''Morphine''' - an analgesic and narcotic drug obtained from opium and used medicinally to relieve pain.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - Healthcare that focuses on preventing and relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve is not strong enough to prevent the back flow on blood into the right ventricle.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - local coagulation or clotting of the blood in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T11:56:14Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of Tetralogy of Fallot (TOF) is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for T-box 1 transcription factor (TBX1). As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a microdeletion of 3 or 1.5 Mb of 22q11.2 region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a haploinsufficient gene. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a 30-bp duplication in exon 9c, a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is dose-dependent, which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the NK2 homeobox 5 transcription factor (NKX2-5 protein). NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute [[#Glossary | '''cyanosis''']] usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] [[#Glossary | '''morphine''']] provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*[[#Glossary | '''Asymptomatic''']] patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a palliative method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the hypertrophy of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) [Xu H, Baldini A (2007) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made surgically between adjacent blood vessels.

'''Annular hypoplasia''' – (need definition)

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Asymptomatic''' - producing or showing no symptoms.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - Blood returning to the heart is diverted through a heart-lung machine (a pump-oxygenator) before returning it to the arterial circulation. The machine does the work both of the heart (pump blood) and the lungs (supply oxygen to red blood cells).

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - existing or taking place, within veins.

'''Morphine''' - an analgesic and narcotic drug obtained from opium and used medicinally to relieve pain.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - Healthcare that focuses on preventing and relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve is not strong enough to prevent the back flow on blood into the right ventricle.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - local coagulation or clotting of the blood in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

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File:Chromosome 22 - TBX1 Gene.jpg

2011-10-12T11:54:19Z

Z3290841: uploaded a new version of "File:Chromosome 22 - TBX1 Gene.jpg": Reverted to version as of 11:37, 12 October 2011

Chromosome 22 - TBX1 gene

This is a diagrammatic representation of chromosome 22. The highlighted and blown-up section is the region in the chromosome contains the TBX1 gene that is affected by the mutation. The mutation involved are microdeletions of base pairs, which are indicated by the red and blue lines on the blown-up part. The blue line represents a 1.5 Mb microdeletion, while the red line represents the 3 Mb microdeletion.

Drawn/created by: John Rommel Hernandez Inspired by the image in http://en.wikipedia.org/wiki/File:NF2.PNG

{{Template:2011 Student Image}}

2011 Group Project 6

2011-10-12T11:52:29Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of Tetralogy of Fallot (TOF) is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for T-box 1 transcription factor (TBX1). As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a microdeletion of 3 or 1.5 Mb of 22q11.2 region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a haploinsufficient gene. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a 30-bp duplication in exon 9c, a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is dose-dependent, which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute [[#Glossary | '''cyanosis''']] usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] [[#Glossary | '''morphine''']] provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*[[#Glossary | '''Asymptomatic''']] patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a palliative method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the hypertrophy of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) [Xu H, Baldini A (2007) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made surgically between adjacent blood vessels.

'''Annular hypoplasia''' – (need definition)

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Asymptomatic''' - producing or showing no symptoms.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - Blood returning to the heart is diverted through a heart-lung machine (a pump-oxygenator) before returning it to the arterial circulation. The machine does the work both of the heart (pump blood) and the lungs (supply oxygen to red blood cells).

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - existing or taking place, within veins.

'''Morphine''' - an analgesic and narcotic drug obtained from opium and used medicinally to relieve pain.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - Healthcare that focuses on preventing and relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve is not strong enough to prevent the back flow on blood into the right ventricle.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - local coagulation or clotting of the blood in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T11:51:05Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of Tetralogy of Fallot (TOF) is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute [[#Glossary | '''cyanosis''']] usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] [[#Glossary | '''morphine''']] provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*[[#Glossary | '''Asymptomatic''']] patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a palliative method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the hypertrophy of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) [Xu H, Baldini A (2007) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made surgically between adjacent blood vessels.

'''Annular hypoplasia''' – (need definition)

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Asymptomatic''' - producing or showing no symptoms.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - Blood returning to the heart is diverted through a heart-lung machine (a pump-oxygenator) before returning it to the arterial circulation. The machine does the work both of the heart (pump blood) and the lungs (supply oxygen to red blood cells).

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - existing or taking place, within veins.

'''Morphine''' - an analgesic and narcotic drug obtained from opium and used medicinally to relieve pain.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - Healthcare that focuses on preventing and relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve is not strong enough to prevent the back flow on blood into the right ventricle.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - local coagulation or clotting of the blood in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

2011 Group Project 6

2011-10-12T11:48:07Z

Z3290841: /* Genetics/Aetiology */

{{2011ProjectsMH}}

=Tetralogy of Fallot=

==Introduction==

[[File:Tetralogy_of_fallot_after_surgery.png‎| thumb | 300px | right | Baby with Tetralogy of Fallot- The morning after surgery]]

Tetralogy of Fallot (TOF) is a congenital heart disease affecting approximately 3 in 10000 people. It is the most common form of congenital heart disease, accounting for about 1 in 10 cases. <ref name="PMID1689816"><pubmed>1689816</pubmed></ref> TOF was named after Etienne-Louis Fallot for his description of the anatomy and physiology of the defects associated with the disease<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>. TOF is believed to be caused by a genetic mutation of chromosomes 5,20 and 25, which impact the development of the neonatal heart. These genetic mutations contribute to the four characteristic defects of TOF:

* Pulmonary stenosis: a narrowing of the blood flow path from the right ventricle to the lungs.
* Overiding aorta: an aorta which is continuous with both ventricles instead of just the left one.
* Ventricular septal defect: the septum dividing the left and right ventricles is incomplete
* Right ventricular hypertrophy: enlargement of the cells in the right ventricle. <ref name="PMID19144126"><pubmed></pubmed>19144126</ref>

TOF patients are given the name 'blue babies' because they often have a slightly blue appearance due to the decreased circulating oxygen levels. Some common symptoms in TOF patients include turning blue while crying, collapsing due to [[#Glossary | '''tet spells''']] during exercise, dizziness and fatigue.

Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the understanding of the cardiac anomalies and treatment options associated with TOF. Currently, surgery is the most successful treatment option, however [[#Glossary | '''palliative care''']] and medical treatment is also available. Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.

Whilst the understanding of this disease has grown greatly, future treatment options are continuously being explored. These include developing durable and efficient surgical procedures, shunts and valves.

==History==

====Early History====
[[File:Dr Etienne Louis Arthur Fallot.jpg| thumb | 180px | right | Portrait of Dr. Etienne Louis Arthur Fallot]]

In '''1671''', Niels Stenson was the first to anatomically describe Tetralogy of Fallot. However, the precise descriptions of the anatomy of Tetralogy of Fallot were done in '''1784''' by William Hunter at St Georges Hospital Medical School in London. His description is as follows<ref name="PMID19683809"/> :

{| style="border: solid 3px #8eb2ec"
|- align="center" style="background:#C0C0C0"
|''“…the passage from the right ventricle into the pulmonary artery, which should have admitted a finger, was not so wide as a goose quill; and there was a hole in the partition of the two ventricles, large enough to pass the thumb from one to the other. The greatest part of the blood in the right ventricle was driven with that of the left ventricle into the aorta, or great artery, and so lost all the advantage which it ought to have had from breathing”''<ref name="PMID19683809"/>
|}

Hunter’s description of the defected heart’s anatomy along with its resulting physiology was further specified and advanced by Etienne-Louis Fallot. However it was Maude Abbott from Canada who coined the term ‘Tetralogy of Fallot’ in '''1924'''<ref name="PMID19683809"/>.

====Contemporary History====

In '''1938''' there was a dawn in surgical therapy for people with heart defects as Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7.<ref name="PMID7888802"><pubmed>7888802</pubmed></ref> [[File:Dr Helen Brooke Taussig.jpg| thumb | 180px | right | Portrait of Dr. Helen Brooke Taussig]]

Later, it was the work of Helen Taussig with her using a fluoroscope which allowed her to determine that children suffering from cyanosis, especially those with TOF, had decreased blood flow to the pulmonary circulation and thus more blood was needed to enter into this circulation. She then put forward a concept that shows the benefits of an ‘artificial ductus’; as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells weeks after the baby was born<ref name="PMID7888802"/>.

It was in the morning of '''1943''' in which Taussig explained to [http://www.mc.vanderbilt.edu/diglib/sc_diglib/biopages/ablalock.html Blalock] and [http://www.blackpast.org/?q=aah/thomas-vivien-1910-1985 Thomas] that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods. It was only a year later in which this belief came into practice as a cyanotic congenital heart experienced the first successful treatment due to surgical means. This technique was conducted on another two cases with the same defect and thus due to such success from the surgeries, the concept had received worldwide success.<ref name="PMID7888802"/>

During the '''1950s''', the rise of open heart surgery began and the era of closed-heart surgery dominance had ceased. It was also during the '''1950s''' to '''1970s''' that surgeons realised the great variance in the anatomy of TOF, thus they had to work out new surgical techniques to accommodate this variation. Also during this period, there was an appreciation by surgeons that whilst conducting such operations in the heart, there needs to be precision in how they conduct their work anatomically. Thus in this 20 year period, there was a number of surgeons who had successfully conducted intracardiac surgeries to infants<ref name="PMID7888802"/>.

During her late years of work Dr Taussig had hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in the infants. At the time the hypothesis received skepticism, however today studies show us that this idea is quite real <ref name="PMID7888802"/>.

====Surgical History====

The first procedures for Tetralogy of Fallot were being conducted from around the '''1950s'''. Due the advances in the areas of medicine which support and maintain surgeries, children born with Tetralogy of Fallot now have a great chance of survive to adulthood<ref name="PMID19683809"/>. In retrospective studies it shows how surgical procedures have improved. From the '''1950s''' till today, the mortality rate from surgery dropped from 50% to less than 2%<ref name="PMID21251297"><pubmed>21251297</pubmed></ref>.

It was in '''1945''' that Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’ and in '''1954''' that Varco and Lillehei repaired a TOF heart whilst doing a open-heart surgery<ref name="PMID21251297"/>.

During the surgeries in the past the surgeons will place a shunt between the pulmonary artery and a systemic artery of a child with Tetralogy of Fallot as this will allow some improvement in the oxygenation of the infant’s blood. It will be later when the individual grows up that the shunt will be removed then the heart will be repaired. Now surgeons prefer to repair the heart in the initial operation to repair the infants heart<ref name="PMID21048055"><pubmed>21048055</pubmed></ref>.

====Timeline====

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot<ref name="PMID19683809"/>
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot<ref name="PMID19683809"/>.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.<ref name="PMID7888802"/>
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time<ref name="PMID7888802"/>.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”<ref name="PMID19683809"/>
|-
|align="center"|'''1930s'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells<ref name="PMID7888802"/>.
|- style="background:#eeeeff"
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart<ref name="PMID7888802"/>.
|-
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1943'''
| Taussig explained to Blalock and Thomas that she believed it would be possible to direct more blood into the pulmonary circulation by conducting surgical methods<ref name="PMID7888802"/>.
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery<ref name="PMID7888802"/>
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery<ref name="PMID21251297"/>
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant<ref name="PMID7888802"/>.
|-
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot<ref name="PMID7888802"/>
|- style="background:#eeeeff"
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants<ref name="PMID7888802"/>.
|}

==Epidemiology==

Tetralogy of Fallot is considered to be a rare genetic disorder. It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered. After the neonatal age, Tetralogy of Fallot is the most frequent cause of ''cyanotic heart disease''. Additionally, Tetralogy of Fallot slightly affects more males than females.<ref name="PMID20091166"><pubmed>20091166</pubmed></ref>

The incidence of TOF seems to occur sporadically, even though there is a 3% risk of reoccurrence in a sibling (without any other first degree relatives affected by TOF) <ref name="PMID19683809"/>. However, Mothers who are 35 years and older have an increased risk that their offspring will have TOF, whilst on the other hand mothers who have 2 or more children have a decreased risk<ref><pubmed>12632214</pubmed></ref>.

Below is a table which shows the incidence rates of TOF in different races<ref><pubmed>12632215</pubmed></ref>:
{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

In regards to genetics, one study showed that in 25% of the cases of TOF there is a microdeletion on Chromosome 22 which has the q11 region within it. Moreover, TOF is associated and frequently diagnosed along side Velocardiofacial syndrome and Di George Syndrome. Interestingly, another study showed that there is a rate of 25% in which patients with this 22q11 mutation eventually develop schizophrenia <ref name="PMID19683809"/>.

Tetralogy of Fallot is also associated with the chromosomal anomalies Trisomy 21, 18 and 13, and also associated with Alagille syndrome which has a JAG1 mutation<ref name="PMID20091166"/>. The most frequently associated genetic anomalies with tetralogy of Fallot is Trisomy 21 and 22q11.2 deletion. Furthermore, mutations in the 5q35 section (which codes for NKX2.5) were found in 4% of TOF patients which are classified as non-syndromic TOF<ref name="PMID19948535"><pubmed>19948535</pubmed></ref>.

In respect to clinical features, 35% of patients with TOF have Ventricular and Atrial arrhythmias. A 30 year follow up period of patients with TOF have shown that 6% of them die due to sudden cardiac death <ref name="PMID21048055"/>.

TOF is treated with surgery (see Treatment section below). When this is conducted before the age of six months, there is a low mortality rate associated with it (i.e. 2%). After surgical intervention is conducted, there is a survival rate of 85-90%<ref name="PMID20091166"/>. It is clearly possible that improvements in the surgical field has allowed the reduction in surgical mortality which was 50% in the late 1950’s to 2% with contemporary surgical methods<ref name="PMID21251297"/>. On the other hand, if a TOF patient decides not to correct their condition, there is a 10% chance they will survive till their age is in the 30s and a 3% chance they will survive till their forties or older. Before surgical interventions were possible, TOF patients usually died within the first few years after birth, and it was rather unusual to see a patient who had survived beyond 30 years of age<ref name="PMID19683809"/>.

In regards to survival statistics, after surgery is conducted to correct TOF there is a <ref><pubmed>16908723</pubmed></ref>:
* 97% chance that the patient will live one year after the surgery
* 98% chance that the patient will survive 20 years after the surgery if they were alive 30 days post surgery
* 90% chance that the patient will survive 30 years post surgery if they were operated on whilst they were children

From epidemiological studies conducted in regards to mortality rates in respect to congenital heart disease in the US between 1979-2005, there was a 40% reduction in mortality that was linked to Tetralogy of Fallot. It is thought that this reduction in mortality was associated to the ‘earlier recognition and treatment of heart failure and arrythmia’ which allowed this change in mortality rates to occur.<ref><pubmed>19853711</pubmed></ref>

==Signs and Symptoms==

'''Cyanosis'''

Normally, red blood cells carry oxygen around the body that is nearly completely saturated with oxygen held by the haemoglobin. When blood loses its oxygen, the colour changes from bright red colour to a colour that is a mix of dark blue and red. This event is known as cyanosis. Cyanosis could occur in situations in which the lungs are compromised due to underlying reasons such as the lungs being infected with chronic obstructive pulmonary disease, pneumonia and exposure to air at high altitudes. In the case of TOF patients, one of the heart defects (i.e. ventricular septal defect, explained further below) allows cyanosis to occur as the blood oxygen concentration is decreased due to the mix of oxygenated and deoxygenated blood in the TOF heart’s ventricles<ref name="Medline Plus - Skin Discoloration">http://www.nlm.nih.gov/medlineplus/ency/article/003215.htm</ref>.

The most important sign of TOF patients is cyanosis. This is when the lips, fingernails and skin of the patient turns a bluish colour<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html</ref>. Additionally during cyanosis, the mucous membranes of the TOF patient may turn blue. Therefore, the cases where dark-skinned individuals may experience cyanosis, the cyanotic event could be observed by change in colour in the nails and mucous membranes, which include lips, around the eyes and gums <ref name="Medline Plus - Skin Discoloration"/>. Cyanosis is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyanosis occurs <ref>http://www.ncbi.nlm.nih.gov/books/NBK367/</ref>.

''''Tet Spells' and Fatigue'''

The word 'Tet spells' is derived from Tetralogy of Fallot, as it is an event experieced by individuals who suffer from TOF. Babies who have TOF can at times enter into these ‘tet spells’, in which there is a sudden drop in oxygen saturation of the blood, causing the baby to turn blue. These 'Tet spells' become apparent when the baby does certain activities such as crying<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An image portraying a 'Tet spell' in an infant can be found here: [http://www.nlm.nih.gov/medlineplus/ency/imagepages/18134.htm Cyanotic 'Tet spell']

In addition to experiencing 'Tet spells', the baby could pass out, become unresponsive to their parents calling or touch, develop fatigue and finally have ''dyspnoea''. Furthermore, children with TOF would develop fatigue quickly and possibly pass out, thus surgeons now repair TOF hearts during infancy and not at adult to prevent such events.<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>

'''Heart Murmur'''

Heart murmurs are sound waves which are clearly audible that come from the vascular system or from the heart which have a round range between 20-2000Hz. It is considered to be produced as a consequence of blood flow within the cardiovascular system which is that is turbulent<ref><pubmed>14979389</pubmed></ref>. In the case of Tetralogy of Fallot, a heart murmur is a common sign which occurs due to the defected heart’s abnormal blood flow through it. However it should be mentioned that heart murmur is not a hallmark for congenital heart defects as many hearts of healthy children also have murmurs<ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. An audio sample of a heart murmur that would be heard in a TOF patient is found in the link below. Also below is a link to the sound of a normal heart beat without murmur and without TOF.

''Normal Heart:'' [http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=1&CourseID=22 First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio] -- ''TOF Heart:''[http://www.easyauscultation.com/cases-waveform.aspx?CourseCaseOrder=5&CourseID=29 Tetralogy of Fallot - Waveform and Audio]

The types of murmurs that can be present in the heart include <ref name="PMID21048055"/>:
:1. '''Pulmonary Insufficiency Murmur''' - which occurs briefly and low pitched in the diastolic phase of the heart beat. This murmur is often missed during a physical examination of the heart because it is heard to hear it and its duration is short
:2. '''Aortic Insufficency Murmur'''
:3. '''Right Ventricular Outflow Murmur''' – can also have a pansytolic (throughout the systole of the heart beat) murmur if there is a presence of ventricular septal defect found in the heart <ref name="PMID21048055"/>.

'''Abnormal Growth and Clubbing'''

Children with TOF do not grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/>. [[File:Finger-Clubbing.jpg |thumb| An example of finger clubbing|300px]]

TOF children may also have ''''clubbing''''. <ref name= "National Heart Lung and Blood Institute - Signs & Symptoms of TOF"/> This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. <ref>http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm</ref>

'''Cardiac and Visceral Problems'''

It should also be mentioned that ''pulmonary insufficiency'' symptoms developed from a TOF heart varies in the degree of pulmonary insufficiency found in that individual. Thus the symptoms that could be presented are of a wide range which could from decline in function to palpitations. Moreover, late symptoms could also develop from the insufficiency which includes right heart failure, exertional dyspnea, ''syncope'' and palpitations. In an event of which right ventricular failure occurs, signs to indicate it include elevated jugular venous pressure, ''ascites'', ''hepatomegaly'', jugular venous distension and peripheral edema.<ref name="PMID21048055"/>

==Genetics/Aetiology==

The genetic etiology of Tetralogy of Fallot (TOF) is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for T-box 1 transcription factor (TBX1). As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a microdeletion of 3 or 1.5 Mb of 22q11.2 region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a haploinsufficient gene. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a 30-bp duplication in exon 9c, a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is dose-dependent, which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the NK2 homeobox 5 transcription factor (NKX2-5 protein). NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene Jagged-1 protein (JAG1 protein), which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a missesnse mutation of the JAG1 gene identified at the 821st base pair. This is a G to A substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

==Pathophysiology and Abnormalities==

{| border="0px"
|-
|The four pathological features of tetralogy of fallot are:

# Pulmonary stenosis
# Overriding aorta
# Ventricular septal defect
# Right ventricular hypertrophy

These features result from the disruption of the aortic and pulmonary outflow tracts. The severity of symptoms is determined by the extent of right ventricular outflow obstruction.<ref name="PMID19144126"/>

'''''Pulmonary stenosis''''' - Pulmonary [[#Glossary | '''stenosis''']] may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). <ref name="PMID14132270"><pubmed>14132270</pubmed></ref> The narrowing of either the valve or the infundibulum obstructs the flow of blood from the right ventricle into the pulmonary circulation. Consequently, this results in a reduced flow of oxygenated blood in the systemic circulation. If the degree of pulmonary stenosis is mild, a left to right shunt forms. (The higher pressure in the left ventricle causes blood to pass through the septal defect into the right ventricle). However, if the pulmonary stenosis is significant, a right to left shunt will form. <ref name="PMID15934690 "><pubmed>15934690 </pubmed></ref> This occurs because the stenosis raises the pressure in the right ventricle and forces blood directly into the left ventricle. This is important because deoxygenated blood can now enter the systemic circulation and problems such as [[#Glossary | '''cyanosis''']], dizziness and fainting can occur. The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Overriding aorta''''' - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly (in front of and above). The aortic valve is located directly above the interventricular septal defect allowing blood from both the left and right ventricles to pass through the aortic valve. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref> This biventricular connection allows both oxygenated (from left ventricle) and deoxygenated blood (from right ventricle) to enter the systemic circulation. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. <ref name="PMID11520451"><pubmed>11520451</pubmed></ref>

'''''Ventricular septal defect''''' - The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. <ref name="PMID19683809 "/> During ventricular contraction, blood from the left ventricle is forced into the right ventricle and then re-enters the pulmonary circulation. This extra volume of blood places pressure of the pulmonary system and compensatory pulmonary [[#Glossary | '''hypertension''']] and right ventricular [[#Glossary | '''hypertrophy''']] may occur. If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience [[#Glossary | '''cyanosis''']] because deoxygenated blood is bypassing the lungs and entering the systemic circulation. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA.</ref>

'''''Right ventricular hypertrophy''''' - [[#Glossary | '''Hypertrophy''']] of the right ventricle is a compensatory response to pulmonary [[#Glossary | '''stenosis''']]. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body. <ref name="PMID3068155"><pubmed>3068155</pubmed></ref>

The diagram on the right shows the blood flow in a normal heart and the blood flow in a patient with Tetralogy of Fallot.
|[[File:Tetralogy of fallot-the 4 defects.jpg|220px|thumb|Tetralogy of fallot-the four defects]]
[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg |360px|thumb| Fetal blood flow in a normal heart and in a Tetralogy of Fallot heart]]
|}

==Diagnostic Tests==

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with [[#Glossary | '''cyanosis''']] and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|[[File:Clinical examination TOF.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions. <ref>http://www.nhlbi.nih.gov/health/health-topics/topics/heartmurmur/</ref>
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh [[#Glossary | '''systolic ejection murmur''']] may be heard and a palpable thrill may be felt along the left sternal border. <ref>Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Robbins Basic Pathology. 8th edn. Saunders/Elsevier: Philadelphia, PA </ref> These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>
|[[File:Heart_murmur_TOF.png‎|200px]]

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device. <ref>Braunwald E. (Editor), Heart Disease: A Textbook of Cardiovascular Medicine, Fifth Edition, p. 108, Philadelphia, W.B. Saunders Co., 1997</ref>
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|[[File:Doctor performing an ECG on patient.png|200px]]

|- style="background:#eeeeff"
|align="center"|'''Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003804.htm</ref>
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.<ref>http://www.nlm.nih.gov/medlineplus/ency/article/003869.htm</ref>
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
| [[File:Some common effects for patients with Tetralogy of Fallot.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray. <ref>Squire LF, Novelline RA (1997). Squire's fundamentals of radiology (5th ed.). Harvard University Press</ref>
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|[[File:Magnetic Resonance Imaging in an adult patient with tof.JPG|200px]]
|- style="background:#eeeeff"
|}

==Treatment/Management==
The treatment for TOF consists of medical therapy, palliative procedures & surgery.

===='''Medical therapy:'''====

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what medications are used for treatment depends upon the degree of [[#Glossary | '''cyanosis''']] in each patient.

*Patients with acute [[#Glossary | '''cyanosis''']] usually carry out knee to chest exercise positions<ref name= "PMID19144126"/> in order to decrease the amount of deoxygenated blood entering circulation. This along with oxygen & [[#Glossary | '''intravenous''']] [[#Glossary | '''morphine''']] provides more blood flow to the lungs and also decreases [[#Glossary | '''ventilator drive''']] . <ref name= "Treatment & Management - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b3></ref>

*Patients with severe cyanosis are usually administered [[#Glossary | '''intravenous''']] propranolol, which causes a decrease in muscle spasms that occur in the[[#Glossary | '''infundibulum''']] (which causes RVOTO). <ref name="PMID19683809"/>

*[[#Glossary | '''Asymptomatic''']] patients do not require any particular medical treatment.

===='''Palliative Procedures:'''====
[[File:The Blalock Taussig Shunt.jpg|thumb|The Blalock Taussig Shunt]]
''The Blalock-Taussig Shunt:''

Total corrective surgery is the most advantageous option for young infants<ref name= "PMID20091166"/>. However, in some instances, infants suffering from [[#Glossary | '''pulmonary atresia''']] or other [[#Glossary | '''anomalies''']] (in addition to TOF) may require a palliative method instead<Ref name= "Medscape Reference - Palliative Procedures"><http://emedicine.medscape.com/article/2035949-treatment#a1156></ref>, because the anomaly changes the candidate’s capability to having total corrective surgery. In some instances, infants with very small pulmonary arteries cannot tolerate corrective surgery and require palliation instead.
The main aim of palliative surgery is to increase pulmonary blood flow and allow for growth and possibly total correction of the pulmonary artery<ref name= "PMID: 19040408"><pubmed>19040408</pubmed></ref>.
By far, the most common procedure is the modified Blalock-Taussig Shut (B-T shunt). This shunt is placed between the Pulmonary and Subclavian arteries (on the same side)<ref name= "PMID: 19040408"/>. The original B-T shunt was placed by[[#Glossary | '''anastomosing''']] a branch of the transected Subclavian artery and the Pulmonary artery<ref name= "PMID: 19040408"/>, but the classic B-T shunt had a disadvantage of [[#Glossary | '''thrombosis''']] that occurred due to the small size of the vessel.

The major advantage of the modified Blalock-Taussig shunt is that it<Ref name= "Medscape Reference - Palliative Procedures"/>:
*Directs partially oxygenated blood from the Subclavian artery to the Pulmonary artery (hence to the lungs for oxygenation), therefore relieving [[#Glossary | '''cyanosis''']]
*Allows for preservation of Subclavian artery
*The shunt can be used on either side
*Allows for easier control and closure of the shunt at the time of complete repair.

Due to this feature, the shunt has an excellent success rate.

Complications of the B-T shunt are rare, but usually include<ref name= "Palliative Operations for Tetralogy of Fallot"><http://www.chdinfo.com/aa/aa112397.htm></ref>:
*Blockage of the shunt – causing the blue colour of the patient to return
*Infection – the ‘foreign’ shunt may become a site for bacteria to implant & cause infection.
*Distortion of the pulmonary artery arises as the child grows and the point at which the shunt is attached to the artery may not grow, causing a kink in the artery to develop.
Other shunts such as the Potts, Waterston and Glenn shunts are either not used or infrequently used today (see table below for more details). <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|'''Image'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the descending portion of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the Pulmonary artery and it is also very hard to close when complete repair is undertaken. <ref name= "Treatment & Management - Medscape Reference"/>
|[[File:Potts Shunt.jpg|120px]]

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the Aorta, to the right branch of the Pulmonary artery. <ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This shunt’s use is more suited to those with Pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|[[File:Waterston Shunt.jpg|120px]]

|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right Pulmonary artery (the classic Glenn shunt). The modified Glenn shunt is where the superior vena cava is attached to the right branch of the Pulmonary artery, which is till connected to the main Pulmonary artery.<ref name= "Palliative Operations for Tetralogy of Fallot"/>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref name= "Treatment & Management - Medscape Reference"/>
| [[File:Glenn Shunt.jpg|120px]]
|- style="background:#eeeeff"
|}

===='''Surgery:'''====

Today, Tetralogy of Fallot can only be treated with open-heart surgery, which is usually performed before 6 months of age<ref name= "PMID19144126"/>.

The goal of surgery is to be able to treat the four [[#Glossary | '''congenital''']] abnormalities associated with TOF. It is also advantageous to perform this surgery at an early age and not wait until the child is older, however the specific timing of the operation is still under some controversy<ref name= "PMID21048055"/>.

[[File:Treatment of TOF surgery.png|300px|thumb|Surgical treatment of Tetralogy of Fallot]]

Surgeries occur under [[#Glossary | '''cardiopulmonary bypass''']] (CPB) and are performed either through the atrium ([[#Glossary | '''Transatrial''']]) or from the right atrium/from the Pulmonary artery (transatrial-[[#Glossary | '''transpulmonary''']]) <ref name= "PMID20091166"/>. Surgical approaches are the most common in patients of all ages.

If a patient has had palliative procedures, these shunts must be isolated and taken down <ref name= "Medscape Reference - Corrective Surgery">< http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b6></ref>, before the actual operation can commence.
In the surgery itself, the surgeon:

* Widens the narrowed Pulmonary blood vessels and the Pulmonary valve itself, hence allowing for greater blood flow to the lungs.<ref name= "PMID19683809"/>
* Repairs the ventricular septal defect using a patch to cover the hole in the septum.<ref name= "PMID19683809"/>

Fixing these two defects also solves the other two defects (the hypertrophy of the right ventricle wall and provides oxygenated blood to the Aorta). When the surgery is carried out during infancy, the incision heals in roughly 6 weeks.

More information regarding Treatment and Surgery can be found here:
|[http://www.youtube.com/watch?v=lRnn1etH2tE&list=FL2TNt6Azyu0rD9Oqj3mYdEg&index=1 Tetralogy of Fallot Repair]|[http://www.youtube.com/user/ChildrensHospPhila#p/u/49/jgLC2QABcxo Treatment Options for Tetralogy of Fallot]

==Prognosis==

If a person has undetected TOF or has not undergone corrective surgery, then the usual outcome depends upon the severity of the Right Ventricular Outflow Tract Obstruction (RVOTO)

A person suffering from severe RVOTO
has a 25% chance to die in the first year, 40% chance of dying within 3 years, 70% chance to die by the age of 10 and a 95% chance of death by the age of 40.<ref name="PMID20091166"/>
[[File:Major causes of death in surgically untreated TOF patients.png|thumb|300px|Pie Graph of major causes of death in surgically untreated TOF patients|]]
The major causes of death in surgically untreated patients are
*Hypoxia spells – 62%
* Cerebrovascular accidents – 17%
* Brain abscesses – 13% <ref name="PMID20091166"/>

If a patient undergoes elective surgery then the patient has a low mortality rate of just 2% (in & directly after surgery) and a long-term survival rate of 85-90%<ref name= "PMID19144126"/>. In the absence of other serious complications, patients are able to live normal lives, shown by the possibility to carry out a successful pregnancy.

Whilst this may be the case many patients go on to develop [[#Glossary | '''pulmonary valve insufficiency''']] <ref name= "Future - Medscape Reference"><http://emedicine.medscape.com/article/2035949-treatment#aw2aab6b6b9></ref> (where upon contraction of the right ventricle, blood flows backwards from the pulmonary arteries in to the right ventricle). This causes the right ventricle to work harder and hence become dilated.

This can lead to hindered function of the right ventricle and cause fatigue.

Another outcome of repair can be a narrowing at the outflow area/branch of Pulmonary arteries<Ref name= "Living with Tetralogy of Fallot"><http://www.nhlbi.nih.gov/health/health-topics/topics/tof/livingwith.html></ref>, which produces high pressure in the right ventricle and can lead to further corrective surgery being undertaken.

Finally, whilst corrective TOF surgery repairs the anomalies, it is crucial that long term follow up with a cardiologist be mandatory to detect any problems, whether they be recurring or new. Hence patients are advised to carry out physical examinations, echocardiography and other exams as the patient matures into a teenager and adult years.<ref name= "PMID19144126"/>

==Future Directions==

In the last decade, several innovations have been developed for possible treatment methods and also management of TOF, these include:

===='''Percutaneous Pulmonary valve replacement:'''====

This has been the most promising and exciting area for the past decade, with majority of focus going into conduit rehabilitation between the pulmonary artery and right ventricle. The replacement is designed for patients who have already had TOF elective surgery and are in need of pulmonary valve replacement. The percutaneous pulmonary valve is composed of a bovine Internal Jugular Vein, with the native valve (bovine) fixed into a platinum stent it is moved along into the right ventricular outflow via fluoroscopic control. This control allows for the valve to be fixed precisely by inflation, using a balloon in balloon method <ref name="PMID19683809"/>. If the percutaneous pulmonary valve proves to have great success and long-term durability, it has the potential to allow for earlier intervention in such cases <ref name="PMID21048055"/> . So far no mortality or late mortality has been registered in the patients tested.

===='''Oral Drug Therapy'''====

Pharmacologic therapy could be used to alter the clinical outcomes that arise with pulmonary insufficiency, which may develop from Tetralogy of Fallot. Scientists and researchers are using MRI imaging technology to see the effect that Nitric Oxide may have upon pulmonary vasodilation and are amidst of trialling similar oral drugs for long-term use. <ref name="PMID20091166"/>.

===='''Genetic Mutation & therapy'''====

Recently, congenital heart patients went under large-scale mutation screenings and several important genes (islet 1, Mef2c etc) [Xu H, Baldini A (2007) <ref><pubmed>17178242</pubmed></ref> involved in cardio genesis, have been identified. Identification of these genes can possibly provide markers for diagnosis of cardiac anomalies such as TOF. Work is also being done for genetic manipulation to be used as a therapeutic tool.

===='''In vitro engineered valves'''====

Finally creation of in vitro tissue engineered valves using human endothelial cells (using allograft techniques) has been shown to have long term durability and also reduce valve degeneration, cusp thickening or pulmonary insufficiency (trivial to mild) <ref><pubmed>16820562</pubmed></ref>. Creation of such valves has great promise for the world of cardiac congenital diseases as it will allow greater options for valve replacement and allow for growth and remodelling as the child continues through somatic growth. <ref name="PMID20091166"/>.

==Glossary==

[[#Introduction | '''Back to top''']]

'''Anastomosing''' - connection made surgically between adjacent blood vessels.

'''Annular hypoplasia''' – (need definition)

'''Anomalies''' - something that deviates from what is standard, normal, or expected.

'''Arrythmia''' - (dysrhythmia) Abnormal electrical activity of the heart resulting in either a fast, slow, or irregular heart beat.

'''Asymptomatic''' - producing or showing no symptoms.

'''Ascites''' – Excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

'''Cardiopulmonary bypass''' - Blood returning to the heart is diverted through a heart-lung machine (a pump-oxygenator) before returning it to the arterial circulation. The machine does the work both of the heart (pump blood) and the lungs (supply oxygen to red blood cells).

'''Clubbing''' – Changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

'''Congenital''' - a disease or physical abnormality present from birth.

'''Cyanosis''' - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. One cause of cyanosis is cyanotic heart disease.

'''Cyanotic heart disease''' - Clinical term referring to a congenital heart abnormality (defect) resulting in lack of oxygen that causes cyanosis (a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin).

'''Dyspnoea''' – Shortness of breath, difficult or laboured breathing

'''Edema/Oedema''' - Swelling caused by the accumulation of abnormally large amounts of fluid in the spaces between the body's cells or in the circulatory system.

'''Hepatomegaly''' – Swelling of the liver beyond its normal size.

'''Hypertension''' - A medical condition where the pressure within the systemic arteries is raised, causing the heart to work harder than normal.

'''Hypertrophy''' - Increase in size of an organ due to an increase in the size of its cells.

'''Infundibulum''' - a funnel-shaped cavity or structure.

'''Intravenous''' - existing or taking place, within veins.

'''Morphine''' - an analgesic and narcotic drug obtained from opium and used medicinally to relieve pain.

'''Murmur''' – Blowing, whooshing, or rasping sounds heard during a heartbeat. The sound is caused by turbulent blood flow through the heart valves or near the heart.

'''Palliative care''' - Healthcare that focuses on preventing and relieving suffering.

'''Palpitation''' – Unusually or abnormally rapid or violent beating of the heart.

'''Pulmonary Atresia''' - a form of congenital heart disease in which the pulmonary valve does not form properly

'''Pulmonary valve insufficiency''' - A condition where the pulmonary valve is not strong enough to prevent the back flow on blood into the right ventricle.

'''Shunt''' – A channel through which blood or other bodily fluid is diverted from its normal path by surgical reconstruction or by a synthetic tube.

'''Stenosis''' - An abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract narrowing.

'''Syncope''' – Brief loss of consciousness associated with transient cerebral anemia, as in heart block, sudden lowering of the blood pressure, etc.; fainting.

'''Systolic ejection murmur''' - A heart murmur heard during the contraction phase of the heart.

'''Tet spell''' - A hypoxic attack due to a lack of circulating oxygen. A tet spell is characterised by shortness of breath and brieff loss of consciousness.

'''Thrombosis''' - local coagulation or clotting of the blood in a part of the circulatory system.

'''ventilator drive''' -

==Internal links==

* Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

* Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

* Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

* Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21

==References==

<references/>

----

{{2011Projects}}

Talk:2011 Group Project 6

2011-10-12T11:46:31Z

Z3290841: /* Genetics/Aetiology */

[[2011_Group_Project_6|'''Group 6''']]: [[User:z3290841]] | [[User:z3291317]] | [[User:z3291324]] | [[User:z3291423]]

{{2011GroupDiscussionMH}}

what do you mean you'll slowly change it? its due in 12 hrs! (z3291324)

Ok this is going to be the new outline of the genetics part, I'll slowly change it here in the discussion so things will be added along the way, also Z3291324 the comments said table, but I'm not planning to put all my info in a table, just the gene profile, the rest will be in text form cause I don't think the information will come across better if I put all of it in a table.

==Genetics/Aetiology==

The genetic etiology of Tetralogy of Fallot (TOF) is still currently unknown and being researched. Even though this is the case, most of the studies done on the disorder have agreed that TOF normally occurs with other developmental disorders, like DiGeorge syndrome, and that the disorder may be caused by multiple mutations in a person’s genome. Here are some of the current suspected genetic mutations that leads to the congenital disease Tetralogy of Fallot.

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22 <ref>http://ghr.nlm.nih.gov/gene/TBX1</ref>
|align="center"| 5 <ref>http://ghr.nlm.nih.gov/gene/NKX2-5</ref>
|align="center"| 20 <ref>http://ghr.nlm.nih.gov/gene/JAG1</ref>
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

===22q11.21===
[[File:Chromosome 22 - TBX1 Gene.jpg|thumb|Chromosome 22 - TBX1 Gene|350px]]

Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot (TOF).<ref><pubmed>11339373</pubmed></ref>. This is why mutation in this region of the chromosome is an important consideration for the genetic aetiology of TOF.

This region of chromosome 22 contains the gene for T-box 1 transcription factor (TBX1). As a transcription factor, it regulates the expression of genes by binding to the regulatory region of the DNA and promote/inhibit the transcription of particular genes <ref><pubmed>9570129</pubmed></ref>. Although the genes regulated by this particular transcription factor is still being researched, it has been discovered that mutation in the gene can lead to the development of TOF <ref><pubmed>20937753</pubmed></ref> <ref name="PMID19948535"><pubmed>19948535</pubmed></ref>

The most common genetic mutation of this gene that results in TOF is a microdeletion of 3 or 1.5 Mb of 22q11.2 region on chromosome 22 <ref name="PMID19948535"/>. The result of this microdeletion is a haploinsufficient gene. This is where there is only a single copy of the gene in one allele, which clinically leads to an abnormal functioning of the protein because a single copy of the gene is incapable of producing enough protein that will allow normal function. <ref>http://ghr.nlm.nih.gov/glossary=haploinsufficiency</ref>

Although microdeletion is the most common mutation in the TBX1 gene that results to TOF, there are other mutational variants that have been observed that resulted in TOF. This variant involve a 30-bp duplication in exon 9c, a region in the TBX1 gene. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract of the gene, resulting to a non-functioning TBX1 protein. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of TBX1 gene, since this gene is dose-dependent, which means that transcription cease as soon as there is enough TBX1 protein. Since the TBX1 proteins are non-functioning transcription of genes that the TBX1 protein is responsible for is not controlled.<ref name="PMID19948535"/>

Mutation of the TBX1 gene may also lead to other phenotype, which includes:
*DiGeorge Syndrome
*Velocardiofacial Syndrome
*Conotruncal anomaly face syndrome

===5q34===
[[File:Chromosome 5 - NKX2-5 Gene.jpg|thumb|350px]]

Studies have shown that at least 4% of TOF patients have NKX2-5 mutation. This is why the mutation in this gene is considered in the development of TOF. <ref name="PMID1714651"><pubmed>1714651</pubmed></ref>

This gene encodes the NK2 homeobox 5 transcription factor (NKX2-5 protein). NKX2-5 protein is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue. <ref><pubmed>7665173</pubmed></ref>. This means the protein regulates the genes responsible for the formation of the chambers of the heart. This is because studies have shown that the NKX2-5 protein is involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation. <ref><pubmed>10587520</pubmed></ref> Atrial and ventricular septation is the formation of the walls that separate the heart into four chambers, while conotruncal septation is the formation of the two great vessels (Aorta and Pulmonary artery) that forms the outflow tracts of the heart.

There are 4 known substitution mutation of the NKX2-5 gene in TOF patients, although one of the mutations has been found to be present in non-TOF patients. <ref name="PMID1714651"/> This includes:
*G to C substitution at base pair 21 = glutamic acid to glutamine amino acid substitution
*C to T substitution at base pair 216 = arginine to cysteine amino acid substitution
*C to T substitution at base pair 219 = alanine to valine amino acid substitution

Mutation of the NKX2-5 gene may also lead to other phenotype, which includes:
*Hypothyroidism
*Congenital non-goitrous
*Atrial septal defect with atrioventricular conduction defects

===20p12.1-p11.23===
[[File:Chromosome 20 - JAG1 gene.jpg|thumb|350px]]

The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) that have some clinical overlap with that of TOF, which are mainly right heart abnormalities.<ref><pubmed>12427653</pubmed></ref> This makes mutation in this gene of special interest when it comes to TOF

The gene is about 36 kb with 26 exons, which are the coding regions of the DNA,<ref><pubmed>9268641</pubmed></ref> and expresses the gene Jagged-1 protein (JAG1 protein), which is a ligand of the Notch receptor <ref name="PMID11869892"><pubmed>11869892</pubmed></ref>. This means that cells/tissues containing the JAG 1 protein are able to communicate with cells/tissues that contains the Notch receptor on its surface. JAG1 Gene is highly expressed in developing mammalian heart, thus JAG1 proteins are present on cardiac cell membranes <ref><pubmed>10556292</pubmed></ref>. With the Notch receptor present on adjacent cells, JAG1 protein is able to communicate with adjacent cells via intercellular signaling. This is because the bond between the JAG1 protein and the Notch receptor leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors, which in turn regulates the transcription of genes that will lead to cellular differentiation and morphogenesis.<ref name="PMID11869892"/>

There is a missesnse mutation of the JAG1 gene identified at the 821st base pair. This is a G to A substitution, resulting in glycine to aspartic acid substitution. This may lead to the formation of cysteine residues that results in the formation of abnormal protein because its structure and stability has been compromised.<ref name="PMID11152664"><pubmed>11152664</pubmed></ref> There are 2 types of proteins resulting from the mutation of the allele, a protein that functions abnormally and a protein that functions normally. The abnormal functioning protein is produced at higher temperature<ref><pubmed>12649809</pubmed></ref>:
*Abnormal JAG1 protein = retained intracellularly and not transported to cell surface
*Normal JAG1 protein = retains function as a ligand to Notch receptor

Mutation of the JAG1 gene may also lead to other phenotype, which includes:
*Alagille Syndrome
*Deafness
*Congenital heart defects
*Posterior embryotoxin

what does everyone think?
http://www.youtube.com/watch?v=_ErZG43lAh8&feature=related at 51 seconds (for physical examination pathophys table) --[[User:Z3291324|z3291324]] 11:24, 11 October 2011 (EST)
actually, this one is probably better http://www.youtube.com/watch?v=3bN7QltwfB0&feature=related at 5 seconds

does anyone know how to properly reference a book? i used robbins basic pathology for some of the pathophys section but im not sure how to reference it--[[User:Z3291324|z3291324]] 11:01, 11 October 2011 (EST)

hey rommel, are you putting these pics on the page? also, can you check out the feedback for your section...did other groups recommend a table for the genetics..or getting rid of the dot points? pics look good btw --[[User:Z3291324|z3291324]] 10:07, 11 October 2011 (EST)

Finally the last image for genetics. That should be it for now I'm really tired. I'll update and clear up the text on the page tomorrow, hopefully you made a comment on the timages and table by then, if not that's fine, but I won't put it in the page until I get a general consensus. --[[User:Z3290841|z3290841]] 19:50, 6 October 2011 (EST)

[[File:Chromosome 20 - JAG1 gene.jpg]]

Here I have another image for the next gene --[[User:Z3290841|z3290841]] 17:51, 6 October 2011 (EST)

[[File:Chromosome 5 - NKX2-5 Gene.jpg]]

Ok guys here you go I changed the image again, hopefully it's better if not tell me asap so I can change it --[[User:Z3290841|z3290841]] 16:36, 6 October 2011 (EST)

[[File:Chromosome 22 - TBX1 Gene.jpg]]

Hey I changed the table for genetics up tell me what you think. If it's good for you guys I'll be putting it in the page. --[[User:Z3290841|z3290841]] 16:02, 6 October 2011 (EST)

Just put up some internal links on the page. feel free to add or remove what you thin is necessary. these are th eones that i just put up
Cardiovascular development abnormalities
http://embryology.med.unsw.edu.au/Notes/heart2.htm#Fallot

Advanced cardiac embryology
http://embryology.med.unsw.edu.au/embryology/index.php?title=Advanced_Cardiac_Embryology

Cardiovascular system development
http://embryology.med.unsw.edu.au/embryology/index.php?title=Cardiovascular_System_Development

Cardiovascular development lecture
http://embryology.med.unsw.edu.au/embryology/index.php?title=2009_Lecture_21
--[[User:Z3291324|z3291324]] 11:35, 6 October 2011 (EST)

Hey this is just a trial run for the table I am doing for the genetics part of our page --[[User:Z3290841|z3290841]] 11:17, 6 October 2011 (EST)

{|style="border: solid 1px #a0a0ff" align="center"
|+ '''Gene Profiles'''
|-
|- style="border: solid 1px #a0a0ff" align="center" style="background:#8eb2ec"
|align="center"|'''Features'''
|align="center"|''' 22q11.21'''
|align="center"|'''5q34'''
|align="center"|'''20p12.1 - p11.23'''
|-
|align="center"|'''Chromosome #'''
|align="center"| 22
|align="center"| 5
|align="center"| 20
|- style="background:#eeeeff"
|align="center"|'''Chromosome arm'''
|align="center"| q (long arm)
|align="center"| q (long arm)
|align="center"| p (short arm)
|-
|align="center"|'''Position'''
|align="center"| 11.21
|align="center"| 34
|align="center"| 12.1 to 11.23
|- style="background:#eeeeff"
|align="center"|'''# of base pair'''
|align="center"| 26,890
|align="center"| 3,208
|align="center"| 36,362
|-
|align="center"|'''Gene Affected'''
|align="center"| TBX1
|align="center"| NKX2-5
|align="center"| JAG1

|}

Hey Rom and jaq, thanks for fixing up the table! :-{) --[[User:Z3291317|Z3291317]] 10:42, 6 October 2011 (EST)

Hey I editted the one that jaqui editted

{| style="border: solid 1px #a0a0ff" align="center"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

Hey guys, I'm currently editing through my sections and adding new stuff, also check the image i placed in the diagnostic techniques part under MRI, i hope it fits properly! also rom the diagram looks a bit complicated, could you simplify it and explain what you are trying to show? thanks --[[User:Z3291423|Jasjit Walia]] 00:53, 6 October 2011 (EST)

test:

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Race'''
|'''Incidence of TOF malformation (per 10,000)'''
|-
|align="center"|''Whites''
|align="center"| 2.85
|- style="background:#eeeeff"
|align="center"|''Hispanics''
|align="center"| 2.31
|-
|align="center"|''Asians''
|align="center"| 2.83
|- style="background:#eeeeff"
|align="center"|''Blacks''
|align="center"| 3.81
|-
|align="center"|''Other''
|align="center"| 3.80
|}

Hey People i re tweaked the table to rom's preferences, and rom you slightly jumbled the structure of the entire table, so i fixed it. Also, in your diagram, it was a bit hard trying to understand the part you try to demonstrate the zone being deleted. Speak to you about it later. Regards --[[User:Z3291317|Z3291317]] 22:50, 5 October 2011 (EST)

Hey guys I just fixed up bits and pieces of the dates on the timeline. Jaqui the table looks really good, and uhm I think I prefer the coplour of jaqui's table. The red looks a but eh to me. By the way thanks furkan for fixing the tables up now all it needs is the reference and I think we can start to get rid of some of the things in the history. Also I made a diagram for genetics so have a geez and tell me things that you like and don't like and/or hate. Also Jaqui I found a yoputube video for your MRI section of the heart I really don't understand what it's showing but I think it'll be really good if we can imbed it and keep it on loop, here's the link http://www.youtube.com/watch?v=UZk9ForCPyE --[[User:Z3290841|z3290841]] 16:30, 5 October 2011 (EST)

[[File:TBX1 gene.jpg]]

just testing out jaz's table too. i think i might have accidentally done this one in blue too --[[User:Z3291324|z3291324]] 21:27, 3 October 2011 (EST)

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Type of shunt'''
|'''Descriptions'''
|'''Reasons for it not being used'''
|-
|align="center"|'''Pott’s shunt'''
| This shunt is a connection that is established between the defending portion of the aorta (on the left side of chest) to the left branch of the pulmonary artery. <ref>http://www.chdinfo.com/aa/aa112397.htm</ref>
| The shunt has a tendency to increase the pulmonary blood flow, pulmonary hypertension, causes blood flow to be preferential to one of the lungs, the shunt causes kinking in the pulmonary artery and it is also very hard to close when complete repair is undertaken <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>

|- style="background:#eeeeff"
|align="center"|'''Waterston shunt'''
| This shunt was placed between the back of the aorta, to the right branch of the pulmonary. <ref>http://www.chdinfo.com/aa/aa112397.htm</ref>
| This shunt’s use is more suited to those with pulmonary artery stenosis and also the procedure is quite difficult to perform. It causes excessive pulmonary blood flow and hypertension and congestive cardiac failure has been found in 20% of patients that have with the Waterston or Pott's shunt <ref name="PMID4813185"><pubmed>4813185</pubmed></ref>
|-
|align="center"|'''Glenn shunt'''
| The superior vena cava is anastomosed via a shunt to the right pulmonary artery (the classic Glenn shunt). The modified glenn shunt is for, the superior vena cava to the right branch of the pulmonary artery, which is till connected to to the main pulmonary artery.<ref>http://www.chdinfo.com/aa/aa112397.htm</ref>
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task. <ref>http://emedicine.medscape.com/article/2035949-treatment#a1156</ref>
|- style="background:#eeeeff"
|}

for the intro, did we decide to make it like a summary of whats to come (so include a bit of epidemiology, symptoms, treatment etc)??--[[User:Z3291324|z3291324]] 21:16, 3 October 2011 (EST)

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Diagnostic technique'''
|'''How the technique works'''
|'''Presentation in a TOF patient'''
|'''Image'''
|-
|align="center"|'''Physical examination'''
| TOF is often diagnosed during fetal life by echocardiography.<ref name="PMID19683809"><pubmed>19683809</pubmed></ref>
If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with ''cyanosis'' and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. <ref name="PMID8272784"><pubmed>8272784</pubmed></ref>
|Insert physical examination image

|- style="background:#eeeeff"
|align="center"|'''Heart murmurs'''
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions.
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh ''systolic ejection murmur'' may be heard and a palpable thrill may be felt along the left sternal border. These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). <ref name="PMID21048055
"/>

|Insert heart murmur image

|-
|align="center"|'''Electrocardiogram'''
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device.
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.<ref name="PMID8272784 "/>
|Insert electrocardiogram image here

|- style="background:#eeeeff"
|align="Chest radiograph'''
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnose many conditions including conditions of the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. <ref name="PMID19144126"><pubmed>19144126</pubmed></ref> The radiograph will also show a right-sided aorta in approximately one-quarter of patients.<ref name="PMID8272784 "/>
|[[File:Chestxrayfallot.jpg|200px]]

|-
|align="center"|'''Echocardiogram'''
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. <ref name="PMID19144126 "/>
|[[File:echo.jpg|200px]]

|- style="background:#eeeeff"
|align="center"|'''Magnetic resonance imaging'''
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray.
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect.<ref name="PMID8272784 "/>
|Insert MRI image here
|- style="background:#eeeeff"
|}
--[[User:Z3291324|z3291324]] 20:29, 3 October 2011 (EST)

Hey Jaq, here is the proposed final table without the references (will be added later). When you have the top part dark red, the reader will cognitively look at the lighter colour as red as the brain will be using the darker colour as a comparative standard (i know its a bit far fetched explanation), i think it will be alright having the colours like this... Look at the new table below, i had fixed some dates up rommel thought were together as it appeared like that in the text, so fiddled with them a bit and added some important dates i should had from before, so this new info would only be found in the table and not in the text, what you guys think?....--[[User:Z3291317|Z3291317]] 19:44, 3 October 2011 (EST)

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1628'''
| William Harvey published his work ''De Motu Cordis'' which portrayed a groundbreaking understanding that the two criculatory systems, pulmonary and systemic, and independant of each other.
|- style="background:#eeeeff"
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot
|-
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot.
|- style="background:#eeeeff"
|align="center"|'''1847'''
| Chevers acknowledged the absence of pulmonary valve in Tetralogy of Fallot hearts.
|-
|align="center"|'''1850s'''
| Peacock was a pioneer in using a stethoscope to discover a cardiac murmur with a heart with pulmonary stenosis.
|- style="background:#eeeeff"
|align="center"|'''1888'''
| Fallot destroyed the idea that cyanosis had always occured due to inability of the foramen ovale to close. Also, he was the one to use the term ''tetralogie'', and furthermore acknowledged that there was no therapeutic treatments for patients of TOF during his time.
|-
|align="center"|'''1888'''
| Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology
|- style="background:#eeeeff"
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”
|-
|align="center"|'''1936'''
| Abbot demonstrated the Chest X-ray, 3-lead electrocardiogram and circulatory and auscilatory diagrams that were produced from a Tetralogy of Fallot heart.
|- style="background:#eeeeff"
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7
|-
|align="center"|'''1943'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells.
|- style="background:#eeeeff"
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|-
|align="center"|'''1950'''
| Beginning of the rise of open heart surgery
|- style="background:#eeeeff"
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery
|-
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant.
|- style="background:#eeeeff"
|align="center"|'''mid 1970s'''
| Advancements in Infant surgery, introduction of prostaglandin therapy and rise in electrocardiography signficantly affected the patients with Tetralogy of Fallot
|-
|align="center"|'''1990s'''
| Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants.
|}

hey furkan, thanks heaps for trying with the table. what do you guys think? maybe our colour scheme would be better as blue and grey. do you think the red looks a bit pink?? --[[User:Z3291324|z3291324]] 19:34, 3 October 2011 (EST)

Hey People i took on Jaq ideas and reformatted the table Rom made (thanks rom!). Its still a work in progress as im going to add many more dates into it so it can accompany the text in the history without having to remove the text. Man coding is annoying lol... regards --[[User:Z3291317|Z3291317]] 18:28, 3 October 2011 (EST)

{| style="border: solid 1px #e75269"
|- align="center" style="background:#f30d39"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot
|- style="background:#ffeeee"
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot.
Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology
|-
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”
|- style="background:#ffeeee"
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent ductus arteriosus in a girl who was aged 7
|-
|align="center"|'''1943'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells.
|- style="background:#ffeeee"
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|- style="background:#ffeeee"
|align="center"|'''1950'''
| rise of open heart surgery
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery
|- style="background:#ffeeee"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant.
Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants.
|- style="background:#ffeeee"
|}

hey rommel! love the table! but are we going to have the table as well as the text? any chance you could make the blue a ligth red..but keep it really similar ie the darker red at the top with the light red and white in the table (so it matches the rest of the colour scheme)--[[User:Z3291324|z3291324]] 17:34, 3 October 2011 (EST)

Hey this is my attempt at making the timeline for the history section. I haven't put in any references cause I just want to check on the things that I put in it if you guys would agree. Feel free to change it, delete some of it and add some stuff in it. Also I just copied the table template from some other group so yeah :)

{| style="border: solid 1px #a0a0ff"
|- align="center" style="background:#8eb2ec"
|style="width:50px"|'''Year'''
|'''Milestones'''
|-
|align="center"|'''1671'''
| Stenson anatomically described Tetralogy of Fallot
|- style="background:#eeeeff"
|align="center"|'''1784'''
| William Hunter gave a precise description of the anatomy of Tetralogy of Fallot.
Etienne-Louis Fallot specified and advanced the description of Tetralogy of Fallot’s heart anatomy and its resulting physiology
|-
|align="center"|'''1924'''
| Maude Abbott coined the term “Tetralogy of Fallot”
|- style="background:#eeeeff"
|align="center"|'''1938'''
| Gross and Hubbard closed off the patent dusctus arteriosus in a girl who was aged 7
|-
|align="center"|'''1943'''
| Helen Taussig using fluoroscope determined that TOF patients suffer cyanosis because of decreased blood flow to the pulmonary circulation. She then proposed the benefits of an “artificial ductus” in TOF neonates, as she believed the closing of the patent ductus arteriosis lead to babies having cyanosis and cyanotic spells.
|- style="background:#eeeeff"
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|-
|align="center"|'''1945'''
| Blalock and Taussig explained the ‘systemic artery-to-pulmonary artery shunt’
|- style="background:#eeeeff"
|align="center"|'''1950'''
| rise of open heart surgery
|-
|align="center"|'''1954'''
| Varco and Lilehei repaired a TOF heart whilst doing an open-heart surgery
|- style="background:#eeeeff"
|align="center"|'''1950-70'''
| Realisation of variance in the anatomy of TOF. This became the period of success for intracardiac surgeries to infant.
Dr Taussig hypothesised that congenital cardiac defects had arisen from the expression of genetic defects found in infants.
|- style="background:#eeeeff"
|}

'''Summary of the Comments made on our draft project'''

- Intro = add picture and basically fix it up
- History = put the quote in the box, add a timeline and less word, put the dates in bold
- Epidemiology = more detail and work
- Signs and symptoms = better ghlossary, change the size of subheadings, explain further, picture for each signs and symptoms
- Genetics = explain better, i.e. the technical details, add a table
- Pathophysiology = reformat
- Prognosis = add a pie chart
- Future Directions = add articles
- Glossary - make some links

here youi go guys, sorry it's a bit late --[[User:Z3290841|z3290841]] 09:44, 3 October 2011 (EST)

hey fru, okay. maybe we should go for alternating colours then. ill try out a couple tonight. also, im just pasting the intro here on the discussion page because im going to edit it either tonight or tomorrow --[[User:Z3291324|z3291324]] 21:24, 2 October 2011 (EST) I like the grey and red border you put around the quote. maybe we can make our colour scheme gray and red. can you try and put that same colour grey into every second box of the diagnostic table. i tried to put in red and grey but for some reason it keeps turning different shades of green!--[[User:Z3291324|z3291324]] 21:46, 2 October 2011 (EST)

Tetralogy of Fallot (TOF), named after Etienne Fallot is a disease that occurs in 3 in every 10000 live births and constitutes to roughly 7%-10% of all cardiac congenital defects today.
TOF is believed to occur due to genetic mutation, which is thought to impact on the development upon the neonate heart. Furthermore, it is believed that the genetic aetiology of TOF is a mutation in one of chromosomes 5,20 and 25. These genetic mutations contribute to the four characteristic defects, in the heart of a patient having TOF:
Pulmonary stenosis
Overiding aorta
Ventricular septal defect
Right ventricular hypertrophy
TOF patients are nicknamed 'Blue babies' because the lack of oxygen being supplied to the body. Some common occurrences for TOF patients include, Infants turning blue when crying, children collapsing due to tet spells during exercise and fatigue.
Etienne Fallot, Helen Taussig and Alfred Blalock have significantly contributed to the scientific community's understanding of the cardiac anomaly and ways to treat it. Today, surgery remains the only way to treat the anomaly, however palliative care and medical treatment is available.
Due to technology advancements, doctors are able to detect TOF more accurately and treat patients quicker, allowing an increase in survival rate and a favourable long term prognosis.
Whilst a lot of knowledge is available on this disease, future directions include developing durable and efficient surgical procedures, shunts and valves.

REPLY 2: You can have the old format, ot have the red and white osscilating colours for the rows, or have both with the borders not that prominent and have the colour changes in the table. Ye i relised your pic was put down, well discuss it at next lab. hows finding other pics going?--[[User:Z3291317|Z3291317]] 10:22, 2 October 2011 (EST)

Do you think the diagnostic table would look better in paragraphs? I think the table is a bit big?--[[User:Z3291324|z3291324]] 13:31, 1 October 2011 (EST)
REPLY: I reckon it will be okmto put into the table if you insert outlines into the table. If you put it into paragraphs, there is gonna be alot of writing in a section that, i think, the reader wouldnt want to read. It your call, see what the other 2 boys think --[[User:Z3291317|Z3291317]] 22:24, 1 October 2011 (EST) thanks fru, do you mean change it back to the old table format? or maybe we could put a light red background for every second row. (i tried doing that but i couldnt find a colour that was light enough and wasnt too pink). also, one of my pics got taken down so i wont upload any til the lab next thursday. --[[User:Z3291324|z3291324]] 08:40, 2 October 2011 (EST)

hey guys, ive fixed up the glossary up to treatment (but i havent done the genetics part). the terms in glossary are in bold at the moment but anyone feel free to change them to a link or anything else.--[[User:Z3291324|z3291324]] 12:48, 1 October 2011 (EST)

'''Page Edits 30 Sep'''
<gallery>
File:2011_Project_Group_6_edits.jpg|Project Page
File:2011_Project_Group_1-11_edits.jpg|All Groups (1-11) Project
File:2011_Talk_Group_6_edits.jpg|Discussion Page
File:2011 Talk Group 1-11 edits.jpg|All Groups (1-11) Discussion
</gallery>

Test table --[[User:Z3291324|z3291324]] 19:02, 30 September 2011 (EST)
{|
|-bgcolor="# AEF572"
| '''Diagnostic technique
| '''How it works'''
| '''Presentation in a TOF patient'''
|'''Image'''
|-
| Physical examination
|TOF is often diagnosed during fetal life by echocardiography (Apitz, Webb, & Redington, 2009). If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation.
|Signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with cyanosis and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. (Somerville, 1993)
|Insert physical examination image
|-
|Heart murmurs
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions.
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh systolic ejection murmur may be heard and a palpable thrill may be felt along the left sternal border. These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). http://ccjm.org/content/77/11/821.full
|Insert heart murmur image
|-
|Electrocardiogram
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device.
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.(Somerville, 1993)
|Insert electrocardiogram image here
|-
|Chest radiograph
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnoses many conditions including the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. (Bailliard & Anderson, 2009) The radiograph will also show a right-sided aorta in approximately one-quarter of patients. (Somerville, 1993)
|[[File:Chestxrayfallot.jpg|200px]]
|-
|Echocardiogram
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. (Bailliard & Anderson, 2009)
|[[File:echo.jpg|200px]]
|-
|Magnetic resonance imaging
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray.
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect. (Somerville, 1993)
|Insert MRI image here
|-
|}

Test:
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==Peer Review==

Group 6:
Nice introduction. The length is right. Perhaps what is missing is general image to make it less wordy.
History seems to be well researched but if you can make into a timeline would be great.
Nice layout in the Signs and symptoms Genetics/Aetiology. You may want to consider more images since the section are quite big. Also, add a description, copyright and reference for the images in the genetics and aetiology.
Well done in the table of diagnostic Tests. Do not forget to add the images.
In the Treatment and management, you may need to add some shading in the table because the lines of the table are not obvious and Prognosis needs more referencing.
In the future Directions, you may consider deleting the in text referencing. Finally, some of references need to re-format.

Well Done. --[[User:Z3284061|z3284061]] 11:53, 29 September 2011 (EST)

'''Group 6'''

* The intro needs some referencing
* An image might be good in the introduction
* Histroy section is good. A timeline might be helpful
* Epidemiology section needs more information
* Good table in Diagnostic Tests, however, images are missing
* An image would be good in either Prognosis or Future directions to break up the text
* Good flow to the project
* Good student drawn picture
* Glossary needs to be completed
* Double referencing needs to be fixed
--[[User:Z3292953|z3292953]] 11:08, 29 September 2011 (EST)

'''''Tetralogy of Fallot (Group 6) Peer Review:'''''

Introduction: Good content, however possibly revise grammar and structure of some sentences. Also, it would engage the reader more if they could visualize what you are saying through an image.

History: This section has the relevant information, however try using a different format to represent your ideas, such as a timeline or a table? Fallot image lacks a student template and images need to have the correct referencing format. Maybe too wordy for history? Try to make it a bit more succinct.

Epidemiology: Slightly short. Can you elaborate?

Signs and Symptoms: Good use of links to redirect the reader to more information. Image is good, however I think you could maybe put more images in this section to break up the text. Try revising some of the sentence structure. Otherwise, the information in this section is good.

Genetics/ Aetiology: This section is good, however some things need to be further explained. Example: “Gene affected = NKX2-5” – could you elaborate on this? Images are good and relevant.

Pathophysiology and Abnormalities: This section is impressive! Images are excellent and help the reader understand what you are describing in words. The fetal blood flow image lacks a student template. This section needs to be referenced.

Diagnostic tests: Obviously a lot of information here. I am sure I do not need to tell you that this section is incomplete. Images need to be added. I am slightly confused as to why there is a reference directly below the table? Couldn’t this be added to the reference list with the other references?

Treatment/ Management: This section is good. Image needs a student template, but otherwise well done.

Prognosis: Good information. However, surely you did not gather all of this information from the one reference? Also, maybe a picture would help to break up the information.

Future Directions: Good idea. This section is good.

Glossary: Could be expanded.

Overall, the page is coming along well. Nice work and good luck with the editing process! --[[User:Z3290808|z3290808]] 10:44, 29 September 2011 (EST)

Tetralogy of Fallot – Group 6

* Introduction is rather disjunct. No images here also. Also no referencing.
* History looks well detailed, however other groups have used a timeline or table to summarize this information. I think this would help it flow better and be more succinct.
* Epidemiology needs some work. No images and the text does not really explain the epidemiology well.
* Signs and symptoms looks well written, however maybe some more images here could be useful. Also a table might better summarize this information. The image used could be better explained also.
* Other sections look well structured and highly detailed. Looks like a lot of work and research has been put in. Images are well explained and correctly referenced.
* The future directions heading could also include some more detail current research projects as well as some comment on the overall direction that this future direction is taking.
* Glossary needs a lot of work to be complete.

--[[User:Z3288196|Z3288196]] 10:44, 29 September 2011 (EST)

'''Peer Review'''
The first striking feature is the long block of text from the start.
You need to break this up with more tables.
Your Genetics/Aetiology section could be laid out more simply. A table with columns for the Gene, gene profile and then description.
In Pathophysiology, you already have the numbered list. Don't put the numbers next description and format this so that each of the following:

Pulmonary stenosis
Overriding aorta
Ventricular septal defect
Right ventricular hypertrophy

are a subheading in your contents.

In treatment and managment, I would suggest that you colour each row of the table differently. I agree that tables without borders look better. However, if is hard to see which bit of information is associated with Pott's shunt, Watersons shunt etc.

Lastly: only 41 references? I would have expected a lot more. The average number for the other groups is in the 125-150 region. You might want to do a bit more research.

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

--[[User:Z3290618|Ziggy Harrison-Tikisci]] 10:41, 29 September 2011 (EST)

Group 6:

Great intro, brief but covers everything. Good amount of references for the information provided
Genetics part was covered well.

The reference under diagnostic techniques should be with the other references and hopefully, by the end of semester there will be images where it says “insert images”

Good use of tables.

Maybe a few more pictures and the page will be perfect.

Evidently there’s been good work put in and the information has been researched well.

9-13 are all the one link so it should be one link not 5 separate links.

Clear and concise

z3332178 =]

'''Peer Review'''

*Introduction: the layout is a bit messy. Maybe get rid of the double spacing. It might also be a good idea to include an image e.g. maybe of a heart. Needs to include more references in this section.
*History section was well written. I suggest putting the quote in a blue box or highlighting it in some way to make it stand out. Try including a table or timeline to summarise the key events and findings.
*Signs and symptoms; Good layout and presentation of information. Easy to follow and understand.
*Genetics: shows it has been thoroughly researched. Like the use of images to compliment the text. Try and put the information in a table. The section is too lengthy in comparison with the other sections. Needs to hyperlink certain technical words to the glossary.
*Pathophysiology: well written. The information is concise and easy to understand. Good use of student drawn images.
*Great idea summarizing the information on 'diagnostic tests' in a table. Get rid of the in text referencing in the table.
*Add a border around the table in the treatment/management section.
*Other sections; good information. The referencing need to be fixed, it's not consistent. Try and include more images or tables in the prognosis, future directions sections to break up the heavy text. These sections seem a bit mundane compared with the rest. Prognosis section required more referencing.
*Glossary; need to be expanded.
--[[User:Z3291622|Z3291622]] 10:06, 29 September 2011 (EST)

‘’’Peer Review’’’

Some places for improvement.

:*Double spacing of paragraphs looks awkward.

:*Introduction does not flow very well. Sentences are very choppy.

:*History section would benefit from a timeline rather than paragraphs as it is a bit hard to follow.

:*In the epidemiology and symptoms sections need some more content. Seems very minimal. Also images?

:*Diagnostic section needs the rest of the information added to its table. “Insert text here”. Also use of bolding or different font sizes would benefit this table.

:*Glossary could be expanded, very minimal.

:*References need to be fixed. There are many that are just a web address. Full citation is needed.

--[[User:Z3217043|z3217043]] 09:19, 29 September 2011 (EST)

Group 6 Peer Review

*Majority of page is in a logical and organised manner however maybe switch aetiology and signs and symptoms to make it flow better?
*History section had good, clear subheadings
*Epidemiology seems brief relative to other sections-perhaps merge with a section or expand on this if possible
*Table in Diagnostic tests-great however an image would help break up the text
*Glossary could be extended further
*Referencing inconsistent
*Image/text ratio is good however layout could be improved
*Overall, a very informative and interesting page. Visual appeal could be worked on but once a few things are adjusted, it will finish it nicely
--[[User:Z3308965|Fleur McGregor]] 09:10, 29 September 2011 (EST)

Group 6

*Introduction is good and very clear, except there are no references, easily fixed but (Y)
*History could be incorporated into a table, or at least, the dates could be bolded or highlighted to establish progress through time.
*Good use of subheadings under ‘Signs and Symptoms’, might be beneficial to include more images as examples of each symptom, but just enough to provide a balance between text and images
*Genetics – well organised information, incorporation of images is excellent, many of the terms mentioned here could be defined in the glossary
*’Pathophysiology and Abnormalities’ – this section definitely needs to be referenced, but good info.
*’Treatment/Management’ – this table needs borders, i was easily confused as to which paragraph i was reading, but great info.
*Glossary could have a lot more terms included.

--[[User:Z3331469|z3331469]] 07:02, 29 September 2011 (EST)

'''Group 6 Peer Review'''

• Nice and simple sub-heading structure. I like the consistency of two images throughout the page. However I feel like you have lots of text with fewer images.

• Introduction is clear and to the point, however where are you references? And an image in this section is always good to give a representation of the abnormality from the start.

• History is really good! Clearly researched very well and good images! Interesting to read. However, the use of a timeline or ‘bolding’ all the dates would make it an easier read.

• Epidemiology is good, however I think you could elaborate more and possibly add a table/graph.

• I personally think that your signs and symptoms would look better displayed in a table. Definitely need more images here, possibly one for each sign/symptom.

• Why are signs and symptoms before the aetiology and pathogenesis of the disease? For me, it’s more logical to explain the cause and how the disease comes about before the signs and symptoms.

• Pathophysiology and abnormalities is a really good descriptive section. Well explained! And good use of images. But where are all the references?

• Diagnostics test has interesting information. Inconsistent referencing system to the entire page, also desperately in need of images to break up all that text.

• Future directions is well summarised, with relevant headings.

• Not really sure what’s going on with your referencing, but you need to have a consistent system throughout the entire page with no doubling up of articles.

--[[User:Z3289829|z3289829]] 02:44, 29 September 2011 (EST)

*Intro: Best not to start off the introduction with stats, people will quickly lose interest. I like how you’ve given a very brief idea of each subheading. This section would benefit from a picture , something to grab your attention.

*History: A timeline would be best, as this section isn’t as significant as the others so it doesn’t need to be in extensive detail.

*Epidemiology: “ It makes up around 7%-10% of cardiac congenital defects. Moreover, epidemiological studies show that it occurs in 3 out of 10000 live births that are delivered” repetitive. Best if not mentioned in introduction, as it is useful fact in this segment. Needs a little more detail, quite short in comparison to other sections.

*Signs and Symptoms: Good use of subheadings, need more images. Loved the audio! Very interesting. This section needs to come in after aetiology though.

*Genetics/Aetiology: Quite extensive, very detailed and understandable, but a lot longer than the other sections, it could do with a bit of trimming. Also the one type of image being used 3 times is not appealing, perhaps hand draw it in different colours or get a different style of drawing representing it.

*Pathophysiology: Like the subheadings and it’s easy to follow the information.The first image is great, the 2nd image could be broken down and hand drawn to compare the normal blood flow with TOF blood flow individually, instead of having the other conditions included. This would make it more clear.

*Diagnostic Test: Table is clearly incomplete. Add images, and add colour. The text is also not referenced. Why is there one reference at the bottom of the table?

*Treatment: Quite detailed and informative. There are many sections missing references above the table.

*Glossary: INCOMPLETE. There’s many more words you can add here.

*References: Links to other pages don’t count as references- that needs to be fixed.

*Overall: Great job. You’re image:text ratio is little unbalanced, as you need more interesting pictures. Needs a few changes here and there as I’ve mentioned above but it’s looking good so far.

--[[User:Z3290270|z3290270]] 02:29, 29 September 2011 (EST)

'''Peer Review'''
* Introduction needs more/any references.
* Use of a quote in History is interesting.
* History sections seems to be too focused on certain specific procedures rather than their significance for the disease itself and the patients.
* Some grammatical errors in various sections.
* Epidemiology seems a bit short...if no other details can be found for it, consider merging it with another section?
* Signs and Symptoms can use more references, but the subheadings used are very fitting and set out the information well.
* The subheadings in Genetics/Aetiology mean nothing to me. Explanations? On that note, the glossary can be more filled out.
* The layout of Genetics/Aetiology can probably be tweaked a bit.
* Pathophysiology is set out very nicely, but it needs references.
* The table in Diagnostic Tests is very succinct, but the section needs some text, if only to introduce/explain the table. Also, there is a random reference at the bottom.
* Treatment/Management needs more references. The table therein is strange, but the information is very well presented.
* The inclusion of a Prognosis section is interesting, but maybe consider putting it within Treatment/Management?
* Inclusion of Future Directions is very good but the references need to be cleaned up.
--[[User:Z3290689|z3290689]] 01:15, 29 September 2011 (EST)

Group 6
*Introduction: well summarised, but paragraphs don’t flow. This section needs referencing and a few terms could be defined in the glossary.
*History: good use of images to break up text. Maybe consider a timeline just to summarise the section since there is a lot of information here to digest.
*Signs & Symtoms: I like the use of subheadings – clearly indicates topics discussed. Maybe consider un-bolding the list of mumurs since they are not headings, just to keep the formatting consistent.
*Genetics: I like the images which are consistent throughout and the use of gene profiles – nice touch.
*Pathophysiology and abnormalities: well written & formatted section. Referencing?
*Treatment/Management: The only thing I would suggest is to add borders to the table so that the rows are clearly separated. I like the external links.
*Perhaps the page needs just a few more images/tables to break up the heavy text. And the glossary should be expanded.

--[[User:Z3332327|Lisa Xiao]] 00:48, 29 September 2011 (EST)

Group 6
Hey, nice progress with your page, all sections have similar amount of content which were interesting

#The key points relating to the topic that your group allocated are clearly described.
#* Introduction: Referencing needs to be improved here
#* History: content is good but too wordy. I think a summary or a simple timeline would be good
#* Epidemiology: Where's the reference for 3/10000 live births?
#* Signs: ok section, but could do with more images here
#* Genetics: If using abbreviations, such as TBX1 gene, you should explain what it is, ie. TBX1 gene (T-box 1). Also need to work on referencing here as well. How about organising all the content in a table? have in columns: gene, gene profile, frequency, etc.
#* Pathogenesis: I'm not quite sure about this, but do you need permission to adapt an image from an article? (I'm referring to the '4 defects' image)
#* Diagnosis: I'm sorry, but this section is a bit bland, though the content is very informative. I think some images here would be good
#* Treatment: Referencing! Also, personally, that green is too bright, maybe find a more neutral, soothing colour?
#The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.
#* Need to find more images, I feel some of the information could be more effectively presented in table formate rather than lengthy text
#Content is correctly cited and referenced.
#* VERY poor referencing, which makes me question the reliability of the content in some sections
#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.
#* needs a lot more images
#Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.
#* research done is evident, just need to reference
#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.
#Develops and edits the wiki entries in accordance with the above guidelines

"What would improve this project...."

* glossary is very lacking in terminology
* need more images
* REFERENCING!

--[[User:Z3291643|z3291643]] 23:25, 28 September 2011 (EST)

'''GROUP 6:Tetralogy of Fallot'''
*Info in the intro is succinct and informative but sentence structuring and punctuation lets this down e.g. "These genetic mutations contribute to the four characteristic defects, in the heart of a patient having TOF" - comma is misplaced here
*"disease that occurs in 3 in every 10000 live births" -consider rephrasing this
*Intro needs an image to draw attention of reader
*While I appreciate the sectioning of the history section, i think that a chronological timeline may be more comprehensive for the reader, I feel that some of the dates are all over the place, also the history of this disease seams to stop at 1950s, could you maybe find more recent findings or contributions
*History images are good but need to be properly referenced and student template is missing from the first image
*I feel epidemiology section is a little underdeveloped, could you possibly find some more stats and compare incidence in several countries?
*Signs and symptoms has good info, but i feel that some sections could be expanded more
*signs and symptoms could use more images to accompany info
*I like the audio links to the heart signs
*Genetics/Aetiology section looks like it has been thoroughly researched, i like the structure of how each gene is dealt with, however, this info could be better formatted in a table and summarised a little more (if you are going to include all this technical info make sure it's explained in glossary maybe), also images in this section need better descriptions in the legends
*Pathophysiology and Abnormalities (I'm not sure if this is the best heading, could maybe be associated conditions or associated abnormalities or even just Cardiac abnormalities), info here is good but could be expanded a little more seeing as cardiac abnormalities seem to be a major manifestation of this anomaly
*Diagnostic tests section could be better placed further up? appears to have some info missing, and in some parts too much text, maybe could be summarised a little. Images could help break up the text, use of a table here is suitable but colour for the side headings could make it stand out a bit more. Referencing really needs to be fixed for this section
*Treatment and management is well researched, however Palliative Procedures could use more referencing esp. at the beginning. Table included is good but could be improved with colour and sectioning
*Prognosis has good inf but lacks referencing

Overall:
*More images are needed to balance out text
*Reference list needs work, don't think it's sufficient to just provide links to websites
*proof reading is needed to fix spelling mistakes, grammar issues and general sentence structure
*Glossary needs finishing, consider linking glossary words to the text and adding any acronyms used
*referencing of some images need to be fixed and student templates are missing in some

--[[User:Z3331556|z3331556]] 22:12, 28 September 2011 (EST)

'''Group 6'''

*The introduction is good but it would be better if there was some referencing.
*The history seemed abit chunky ? maybe a summarised version in a form of a timeline would be good. But overall the use of images is good, it breaks up the heavy text more.
*Epidemiology was abit too short, maybe expanding on why it is this pattern and etc would be a good idea.
*Signs and Symptoms had a nice summary of information. Maybe more pictures would make it more easy on the eyes because this section is quite big on the info. But the audio is a interesting idea!
*Genetics - Firstly, maybe get rid of mark's post. Secondly the layout of information is not that appealing, maybe you could underline the headings to make it more definite. Lastly, the use of images is good! it is very consistent for all genes.
*Diagnostic Tests section was not referenced! If it was then this section would be a winner, if it was completed!
*Overall, it looks like you guys have done alot of research. Good job!

--[[User:Z3330313|z3330313]] 00:01, 29 September 2011 (EST)

'''Group 6:'''

•Very text heavy, perhaps an image in the introduction could be added to grab the attention of the reader and create a better balance between text and images.

•Also, there are no references in the introduction. The source of this information needs to be references properly.

•The history section is worded well, though it may be more visually appealing and better formatted in a timeline. Also it seems to stop at the 1950s period. Is there no other recent research or developments made that could be added to bring the timeline up to date?

•The epidemiology section is quite short

•Good description of the signs and symptoms and good use of external links in this section for further information

•I like the diagnostic tests table, although it is incomplete at the moment, when the images and other information is added then this section will be very well done. Just make sure that it is referenced properly though, because it seems to be lacking referencing at the moment.

•Glossary needs to be completed and a number of the references are repeated

•Good work overall, some sections just need to be fixed up and completed and some more images added, but the overall formatting seems fine.

--[[User:Z3332183|z3332183]] 21:30, 28 September 2011 (EST)

'''Group 6'''

'''*The key points relating to the topic that your group allocated are clearly described.'''
All main sections are there. History is well done, perhaps a time-line could be used?

'''*The choice of content, headings and sub-headings, diagrams, tables, graphs show a good understanding of the topic area.'''
Good use of headings, subheadings in history was well used.

'''*Content is correctly cited and referenced.'''
File:Finger-Clubbing.jpg, File:TBX1.jpeg, File:NKX2-5.jpeg, File:JAG1.jpeg and File:Normal fetal blood flow and Tetralogy of Fallot.jpg should be referenced properly.

'''*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.'''
Well done student image with good explanation. More images would be good. Include more terms in glossary. Table in diagnostic tests has too much text. Table should be used to summarise, put main block of text outside of the table.

'''*Evidence of significant research relating to basic and applied sciences that goes beyond the formal teaching activities.'''
Prognosis needs more referencing.

'''*Relates the topic and content of the Wiki entry to learning aims of embryology.'''
Good information in genetics, but maybe relate the symptoms to problems? (eg: what does Conotruncal anomaly face syndrome mean for the person/fetus?)

'''*Develops and edits the wiki entries in accordance with the above guidelines.'''
Has developed wiki according to guidelines but some changes could be good.

--z3329495 21:18, 28 September 2011 (EST)

'''Peer Assessment Group 6-Tetralogy of Fallot'''

* An image in 'Introduction' will make the beginning of the page more lucrative
* History might work better as a timeline, with bullet points and bold the dates so it is easier to follow.
* Surgical history and Contemporary History has a lot of information, some of it overlaps.The whole section could be replaced by a 'easy to follow' timeline. Good pictures in history.
* Are you going to expand on 'Epidemiology',? Maybe talk more about the actual pattern of occurrence rather than just a couple of observations from epidemiological studies?
* Are you also adding a description for Aortic Insufficency Murmur? The other three heart murmur types have an explanation except for this one.
*There are too many gaps in between the lines, makes the page look a bit sparse.
* Genetics looks quite full on. You may want to add more distinct subheadings to make it easier to follow and keep the reader's attention
* 'Abnormalities' looks great however you might want to change the italics to just bolded headings, makes the page look more consistent. Also make the numbers bold if you are going to have the text following the number bold.
* Though in number 4 under 'abnormalities' can you give a quick definition on what hypertrophy actually is?
*Even though the table is coming along make sure you take the reference off from the bottom of the table and add pictures. It looks like a work in progress. Also the referencing style is different to the rest of the page
* The student drawn pictures under treatment is nice.
* The table is also quite succinct
* 'Future directions' doesn't sound great as a heading. Use something more appropriate to the context
--[[User:Z3308968|Tahmina Lata]] 19:21, 28 September 2011 (EST)

'''Peer Assessment Gr 6'''
*History – what has been done in the last 50yrs? It seems to stop around 1950.
*Signs and symptoms- needs to be edited so it flows better, avoid long wordy sentences – just break them up into 2 (e.g abnormal growth part). Do you have a pic of a blue baby?
*Genetics- need a bit more space between each gene section, just to make it really clear (e.g. between the end of 5q34 and 20p12.1)
*Diagnostic tests table is good (but incomplete), perhaps consider using colours like other groups has? But the bright green of the shunt table is too bright, it hurts my eyes haha.
*References under the reference table needs to be fixed – do you want them to be in the table, or a list of them or what? Same for the references in the future directions section.
*Very well researched and thorough explanations
*Maybe expand the glossary?
*Reference section has some that double up (one after another) – there is a way to fix this and condense it.
*Do you have some photos of real hearts that have been affected by this disorder?
--[[User:Z3332824|z3332824]] 17:46, 28 September 2011 (EST)

'''Group 6: Peer Assessment'''
* It would be good to see more images
* The introduction would be more engaging if it had an image
* The history section is informative however would be nicer in a chronologic fashion. May be a table?
* The extra surgical history makes it clear that surgery plays an important role. Good
* Signs and Symptoms and genetic abnormalities are good overall. Many of the terms need to be added to the glossary though and it might be better to put aetiology first.
* It's a quite big and text heavy table in your diagnostic section. May be you can make it shorter, put pictures in

* I found quite a few words that should be in the glossary
* There is no title for your reference section and it looks like you should have more references for the amount of text that you have written
* Overall your page is very informative, good content. You need more images, appropriate referencing and a more complex glossary. --z3279511 17:11, 28 September 2011 (EST)

'''Group 6 Peer Review'''
* Good introduction, although an image straight up would be nice!
* History is presented well, although a table format at the end that summarises everything you have said would be nice. Also, does the history stop around the 1950's? It seems like there has been nothing done on it until 1970/1980? Hence, the table format would be nice if it appears that I've missed information.
* Epidemiology section is really quite short. Is there nothing more that can be said on it? Does it have preference to specific race?
* Signs and symptoms - from the way that the page is formatted it appears that you've gone down onto the level 4 headings with 4 ='s paraphrasing each heading. Try to use 3 or so just to make sur e the headings are larger and each subsection can be identified.
* The genetics/aetiology section should be explained better; whilst this is aimed at academics, it is almost impossible to understand the information pertaining to the genetics section.
* The pathophysiology and abnormalities section is well explained, and the diagram is excellent to show exactly where the problem lies. A well done section, and a well-selected image for the blood flow patterns.
* Diagnostic tests: Still need to insert those images on the right hand side column! Also, ensure that the referencing is done in the correct format - this section still needs work.
* Treatment/Management section is done well, with a good balance between text and table.
* Current and Future research: Perhaps more dates? The formatting here also needs to be fixed up, and try to have dates on the papers that you are quoting from (although I understand it's difficult without the references in place)
* The glossary section needs more terms added to it! Especially from the genetics/aetiology section which is already terribly difficult to understand.
* Referencing section is quite short - but understandably the whole project feels like the referencing just needs to be finished.
* Overall a nice-looking project with a lot of promise. The spacing and format of the project makes it easy to read - perhaps more images and the use of some tables might also assist in the presentation of this project.
--[[User:Z3288827|Leonard Tiong]] 10:49, 28 September 2011 (EST)

'''Group 6'''

*My first impression is that this project is lacking images. There is way too much text in comparison to images.
*An image would nicely complement the introduction
*I feel that history would work better in a timeline
*Epidemiology needs a table/graph
*Good links in signs/symptoms although another image would be nice
*Genetics needs to be explained a little better
*Student drawn images were great- obviously a lot of effort has been put into these
*Diagnostic test table needs an image and needs to be referenced properly
*Again, an image is needed for prognosis
*Glossary needs to be extended
*Overall a good project but you need to fix a few things

'''Group 6'''

*Introduction: the contend is ok, but the structure could be clearer

*History: too text heavy, a timeline would be nice

*Epidemiology: more content would be good

*Symptoms: the picture could be more general

*Genetics/ Aetiology: the structure could be better, maybe use some more subheadings, and put the gene profile in tables

*Pathophysiology: you need references

*Diagnostic tests: why does it say “insert images”, that should be fixed

*Treatment/ management: looks like there are some references missing? Deleate “Want to learn about more surgery and treatment methods?”, the contend is good, types of shunt would look better as a table

*Prognosis: references missing? good use of subheadings,

*Glossary: incomplete
--[[User:Z3387190|Z3387190]] 21:52, 27 September 2011 (EST)

'''Group 6 peer assessment'''
*Introduction is clear though lack images where a image of example of a blue baby would suffice
*History begins clearly though becomes about surgical history instead of the disease, where time line is not even present of how understanding of this disease improved.
*Epidemiology should be expanded either the genetics of the disease, in general have more information of the causes, incidence and distribution of the disease.
*Signs and symptoms poorly structured and requires more images also doesn’t have an introduction to the signs and symptoms. Although the extra links to comparison of the heart is useful and nicely used.
*Pathophysiology should add supplementary information to back up all the information.
*Diagnosis please add the images, while there is the content though no image following also first box has “insert text” very confusing.
*Treatment/management indicate the separation of surgery and other treatment types in the introduction which is lacking otherwise all is A ok
*Glossary needs to be referenced to other sections of the web page also expanded as most language used is unknown without a dictionary.
*Referencing needs to be fixed as links is not proper referencing also the repeats need to be removed
z3332250 23:53, 26 September 2011 (EST)

===Comments on Group Project 6===
'''Strengths:'''
*The flow between sections and sub-sections is good with appropriate placements of headings and sub-headings.
*Some of the references have good use of multiple referencing so as to avoid duplication.
*The external links under signs and symptoms is very apt and will interest readers.
'''Weaknesses:'''
*Almost half of the references are not properly formatted.
*Some of the words that should be in the glossary are not under that section e.g. Velocardiofacial, Conotruncal, Hypothyroidism, nengoitrous, embryotoxon.
*Punctuation in some sections can be better.
'''Specific corrections:'''
*”muattional” under 22q11.21 sub-heading is spelt incorrectly.
*”cyamnosis” under signs and symptoms is spelt incorrectly.
*”enlargenemt" under clubbing is spelt incorrectly.
*Insert a timeline under history to provide a summary.
*It might be better to have genetics section before signs and symptoms.
*Under Treatment/Management, it will be good to put “medical therapy”, “palliative procedures” and “surgery” as sub-headings.

--Z3389806 08:03, 26 September 2011 (EST)

'''Group 6 Critique'''

#• Introduction is ok, however it needs to be structured a lot better than what it is
#• History is interesting
#• Epidemiology needs a lot more detail. A few lines is not good enough
#• Signs and Symptoms is ok
#• Genetics needs to be explained a lot more clearly than what it is
#• Abnormalities is ok
#• Diagnostic tests table is impressive
#• Treatment/management section is very good
#• Prognosis and future directions section is great
#• Glossary is incomplete. Check the first term and fix this

--[[User:Z3289991|Robert Klein]] 19:05, 24 September 2011 (EST)

'''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!

Group 6-
* No way near enough images. As I scrolled through there was HEAPS of text and only a few images, all of which are on the right hand side. It would be better if they were scattered around
* An image in the introduction would be helpful
* What are ‘tet spells’? mentioned in the introduction (described later but when seen in the introduction it looks like a typo)
* History would work better as a list of dates rather than paragraphs. I do like the section at the top with the quote though
* Epidemiology needs an image- perhaps a table or a graph.
* Signs and symptoms could do with another image to visualise the clinical manifestations
* I really liked the audio clips but the first one didn’t work on my computer? I couldn’t hear anything. Not sure if it was just me
* I think you can come up with a better way of formatting the genetics section. Maybe a table? The information is good it just looks a bit funny
* The pathogenesis doesn’t actually say HOW is happens in infants. Is this a condition formed during embryonic development or after?
* The diagnosis section is far from complete. This needs to be corrected
* Diagnosis section is also not referenced properly
* Why is there a reference at the bottom of the diagnosis section?
* As funny as this was: ‘Want to learn about more surgery and treatment methods? Check here!’…. maybe not appropriate sorry. It should be a little more formal. If you want the reader’s attention- try colour.
* Prognosis- image needed please. Maybe a graph?
* The glossary also needs to be extended
* The references need to be tidied up- there are also not many?
* You need to reference your images properly. ‘normal fetal blood flow and tetralogy of fallot’ is an example. You have but the copyright but not the reference. The web address is not a reference
* You are clearly on your way with the project but more work is required. You need to FINISH the content and format it a little better with more images.

''Group 6 Assessment'''
*First, I’d like to note good job on using a reference more than once in the correct way instead of referencing the same thing multiple times. At least this is done in the first few sections. First time I’ve seen this done correctly!
*The introduction, however, has no references whatsoever. Where did this information come from?
*It might also be good to add a simple picture in the introduction section so it looks more appealing.
*Good information included in the history section. It might look better if this were laid out in a bullet format though.
*The epidemiology section looks rather bland. Not only is there not a picture, but there also isn’t very much information included. Think about what else you could include here or what you could go into depth about.
*The signs and symptoms section has good information, but it might be a good idea to represent this information in a better format, possibly in a chart, with pictures of each symptom included in the chart.
*Finger-clubbing.jpg also needs a detailed description still.
*Good organization and format under the Genetics section.
*Under the pathyphysiology and Abnormalities section there are no references made. Where did this information come from? Diagnostic Tests and Treatment also needs more referencing.
*Pictures still haven’t been inserted into the Diagnostic Tests chart.
*More referencing is needed for the Prognosis section. Also, does the glossary terms need to be referenced?
*It would be a good idea also to have the glossary terms linked with the words in the wiki page, so that the reader can easily get access to the word in the glossary. References 7-14 are the same reference. Fix these so they are under one single reference number.
*For the references given throughout the wiki, there isn’t any consistency in how the [#] is given. The [#] is sometimes right after the sentence, sometimes a space is given between the sentence and citation number, and the end of the sentence (period or comma) is sometimes before or after the reference #...
*Overall, there is a substantial amount of information given within this page, which is good. I like the basic format of everything and most of the pictures which are included. Just work on weaving everything together better and referencing things correctly. Good job!

--[[User:Z3391078|Z3391078]] 15:32, 27 September 2011 (EST)

'''Group 6'''
* Nice overall structure and good use of headings and subheading. It gives the page a nice flow.
* INtroduction is nice and straight to the point and gives the reader a good overview of your topic.
* I like the historical section with interesting subheadings used, maybe you could add a timeline just to simplify the info.
* Signs and symptoms nicely arranged. could you add some more pictures here?
* Pathophysiology and Abnormalities section need to have the references accompanying the information. Just so the read can identify where all the info is from.
* The diagnostic tests table would be nice with some colour and when the images are it will look complete. It's a little text heavy for a table maybe try bullet points. also the referencing system has changed in this table? and a little unsure of the reference at the bottom of the section?
* Treatment/Management section is nicely arranged.. could you add another picture here just to compensate for the amount of text. the table really brightens up the page!
* Future directions section is nicely summarised and I like the tone of voice used here. just make sure the referencing is correct as it is a little confusing and interrupts the flow of the section.
* Maybe the use of similar tables and colour scheme will increase the continuity of the page.
* Make sure your references are not doubled in the list.
* Ensure all of your pictures are correctly referenced.
* Make sure all acronyms and scientific wording is in the glossary.

*'''Intro''': What's a tet spell?
*'''History''': Very good in general. Not sure it makes sense to split it into 2 parts, with surgical being separate? I think it would work just as well combining the two.
*'''Edidemiology''': Looks fine
*'''Signs and Symptoms''': Otherwise good, but considering you have a whole subsection entitled clubbing, I'd suggest explaining what it is right there, and not just in the glossary.
*'''Genetics/Aetiology''': Love the detail and depth, though the more technical terms should be explained in the glossary. Tiny comment: "there is only a single copy of the gene in one allele" - I know what you're trying to say, only one allele is functioning, but saying it like this kinda means, this allele only has one copy of the gene, whereas usually there are multiple copies of a gene in one allele, which is, as far as I know, not the case (that would just be contradictory, as an allele is a copy/varient of a gene).
*'''Pathophysiology and Abnormalities''': Very good, nice use of figures.
*'''Diagnostic Tests''': Not sure I like the table. It is just a hell of a lot of text... in a table. It doesn't really help give an overview, maybe just have subheadings, with (once you have an image) a picture on the side? Also, referencing needs fixing.
*'''Treatment/Management''': Very good, nice amount of detail. Again not sure a table is required. Also, the colour is a bit in your face, but that might just be me. I like the links at the end.
*'''Prognosis''': Content seems fine. A bit odd there's only one reference?
*'''Future directions''': Otherwise seems fine, though referencing needs fixing.
*'''Glossary''': A bit poor. More technical terms need to be explained.
*General: The last few sections lack some figures, it is just a lot of text. The content in general (as in of the whole project) was really good, so well done!

'''Peer Assessment: Group Project 6'''
*The introduction and the section on pathophysiology and abnormalities have no references. This needs to be rectified.
*The introduction and some of the history section have short paragraphs that are only one sentence long and would be improved, both for formatting and information purposes, by incorporating them into the rest of the information.
*Inserting a small timeline in the history section would make the sequence of events more accessible to the reader.
*Some sentences are too long such as, 'Children with TOF don’t grow at the rate of normal children as whilst breastfeeding in infancy, the babies would get tired quicker and during the growth of the infant, normal functionability of the heart and oxygen saturated blood is needed for proper growth'. This sentence could be broken up and also improved by a greater explanation of why the process of growth is abnormal in TOF.
*Maybe explain more about what 'clubbing' is.
*In the diagnostic tests section the images need to be inserted and needs to be properly referenced. The information is good but as noted one section is totally void of text.
*The section on prognoses needs proper referencing.
*The section on future directions is well written, however the referencing needs to be adapted to the wiki format.
*Under the information in some of the images you have uploaded such as in the portait of A. Fallot, you still need to add <nowiki>{{Template:2011 Student Image}}</nowiki>.
*The project is informative, however formatting and referencing are issues that need to be addressed.
--[[User:Z3217345|z3217345]] 22:23, 27 September 2011 (EST)

'''Group 6:'''
* Introduction: Maybe briefly explain the symptoms and the physiological implications of a tet spell and what palliative care is, alternatively hyperlink these words to the signs and symptoms and treatment sections. There are also a few mistakes such as no space after commas “chromosomes 5,20 and 25.” and an incorrect capital letter after a comma “TOF patients include, Infants turning blue”, just make sure to correct these little mistakes by re-reading this section. An image here would also be good.
*History: The history you do have is very comprehensive and easy to read, however the dates get lost in amongst the text. If you bold the dates or include a brief table after the text it will help the reader to track the history better.
*Epidemiology: Very short, could you maybe elaborate to why TOF affects slightly more males than females?
* Signs and symptoms; the information here is very good, it could be improved with the use of more images. I’m not sure if it’s just me or not but I couldn’t hear anything in the normal heart video but the TOF heart video was fine?
* Genetics: This section genuinely scared me, it is a lot of text and a lot of scientific text at that. I found it difficult to read and ended up skipping over this section. Maybe try explaining the genes in your own words. The images do help though so maybe make them bigger. I did find a little typo “gene taht results to TOF” so make sure you proof read once you’ve edited again.
* Pathophysiology and abnormalities is done really well with great visual aids (second image needs to include <nowiki>“{{Template:2011 Student Image}}”</nowiki>). Only suggestion is to leave the sub-headings just bold - no need for italics.
* Diagnosis is obviously unfinished but once the images have been added, the blank text has been filled and some colour is added to the table, I think it will be a great section.
* Treatment and management: The image here is also missing the student template. Spelling mistakes found so proof reading is required “oxygen & intravenous morphine to provides more blood flow”. The table here could be coloured to liven up the page.
* Prognosis is done well but maybe a pie graph could be inserted to show the major causes of death in surgically untreated patients as a visual.
* Future directions is also very good – the referencing just needs to be fixed.

--z3290815 20:31, 28 September 2011 (EST)

'''Peer Review'''

* really well done
* format and structure of the wikipage was consistent throughout

--[[User:Z3060621|z3060621]] 21:36, 28 September 2011 (EST)

Test:

{| style="color:black; background-color:#ffffcc;" width="85%" cellpadding="10%" cellpadding="15%" cellspacing="0" border="1"
| colspan="2" | '''Diagnosis'''
|}

--[[User:Z3291423|z3291423]] 11:57, 22 September 2011 (EST)

Hey Jaz, thanks for letting me know...my english can fail me at times.....lol...fixed it up... regards--[[User:Z3291317|Z3291317]] 18:49, 18 September 2011 (EST)

Hey guys! i just realised that the caption of helen taussig and ballot say portraight....not PORTRAIT!?!! i tried to change it but it don't really know how..anyone have any ideas to this?! :S thanks --[[User:Z3291423|z3291423]] 00:06, 17 September 2011 (EST)

Table Test! --[[User:Z3291423|z3291423]] 22:16, 16 September 2011 (EST)
{|
|-bgcolor="# 99FFFF"
| '''Type of Shunt'''
| '''Description'''
| '''Reasons for it not being used'''
| '''Image'''
|-
| Pott’s Shunt
| This shunt is a connection that is established between the lower part of the Aorta (on the left side of chest) to the left branch of the Pulmonary artery.
| The shunt has a tendency to increase the pulmonary blood flow and it is also very hard to close when complete repair is undertaken
| Insert image
|-
| Waterston Shunt
| This shunt was placed between the back of the Aorta, to the right branch of the pulmonary.
| This shunt’s use is more suited to those with pulmonary artery stenosis and also the procedure is quite difficult to perform.
| Insert Image
|-
| Glenn Shunt
| The Super Vena Cava is anastomosed via a shunt to the right pulmonary artery.
| This procedure is very complicated and difficult to perform, also complete repair becomes a laborious task.
| Insert image
|}

Table test (fingers crossed!) --[[User:Z3291324|Jacqueline Ellero]] 10:49, 15 September 2011 (EST)

==TOF diagnostic techniques==

{|border="1px" cellspacing="1" align="center" cellpadding="5" style="background:seashell"

|+ This table describes different diagnostic tests for TOF
! Diagnostic technique !! How the procedure works !! Presentation in TOF patient !! Image

|-
|Physical examination
|TOF is often diagnosed during fetal life by echocardiography (Apitz, Webb, & Redington, 2009). If TOF is not detected during fetal life, certain signs and symptoms at birth may alert the need for further investigation. These signs and symptoms include mild to moderate cyanosis, which worsens when the baby cries, difficulty feeding and difficulty gaining weight. However, TOF often goes undiagnosed until adult life. Most adult patients will appear normal, however, some may present with cyanosis and clubbing of the fingers. The jugular venous pressure is usually normally (raised jugular venous pressure often indicates right ventricular failure). If the aorta is pushed to the right (so it is continuous with both the left and right ventricle), a lift below the right sternoclavicular joint may be noted. (Somerville, 1993)

|Insert text here
|Insert physical examination image
|-
|Heart murmurs
|Heart murmurs are sounds caused by the turbulent flow of blood. They are heard using a stethoscope. They are often the result of problems including valvular stenosis (narrowing of valves), valvular regurgitation (leakage of valves due to incomplete closure) or defects in the heart wall allowing blood to flow in unusual directions.
|Examination of the heart of a patient with TOF may reveal a loud second heart sound (produced by the closure of the pulmonary valve). A harsh systolic ejection murmur may be heard and a palpable thrill may be felt along the left sternal border. These sounds occur because the pulmonary outflow tract is obstructed. Although this murmur is often present, sometimes it may be short or difficult to hear and is often missed on physical examination. A pansystolic (occurring throughout the whole of systole) murmur may also be heard. This type of murmur occurs due to the ventricular septal defect between the left and right ventricles. The increased pressure in the left ventricle forces blood back into the right ventricle, causing a murmur, which lasts the whole of systole (contraction phase). http://ccjm.org/content/77/11/821.full
|Insert heart murmur image
|-
|Electrocardiogram
|Once TOF is suspected, electrocardiogram and chest radiographs are performed. Electrocardiography is used to assess the electrical activity of the heart. The electrical activity is detected by electrodes, which are placed on the skin of the patient and recorded by an external device.
|The electrocardiogram is extremely important in detecting a right bundle branch block (a block in the electrical conducting system of the heart), which is common in patients with TOF. An electrocardiogram will also reveal a heart that is deviated slightly to the right and an enlarged right ventricle due to the ventricular hypertrophy.(Somerville, 1993)
|Insert electrocardiogram image here
|-
|Chest radiograph
|A chest radiograph (or chest x-ray) uses ionising radiation to develop an image of the patient’s chest. It is used to diagnoses many conditions including the thorax and structures within the thoracic cavity including the heart, lungs and major blood vessels entering and leaving the heart. Chest radiographs are often used to screen for certain diseases but further tests are required for a definitive diagnosis.
|In a patient with TOF, a chest radiograph will demonstrate a prominent right ventricular shadow, giving the heart a boot-like appearance, which is typical of patients with TOF. The right ventricular hypertrophy causes the apex of the right ventricle to rise on top of the relatively unfilled left ventricle, giving the heart its boot-shaped appearance on examination. (Bailliard & Anderson, 2009) The radiograph will also show a right-sided aorta in approximately one-quarter of patients. (Somerville, 1993)
|Insert CXR image here
|-
|Echocardiogram
|An echocardiogram (also called a cardiac ultrasound) is performed to confirm the above findings. Echocardiography uses ultrasound to produce two-dimensional (and now also three-dimensional) images of the heart. It assesses cardiac tissue, valve function, the velocity of blood flow and any abnormal communications within the heart.
|The echocardiogram identifies important abnormalities of the heart including obstruction of the pulmonary outflow tract, the size of the pulmonary arteries, the degree of aortic override and the size of the defect in the interventricular septum. (Bailliard & Anderson, 2009)
|Insert echo image here
|-
|Magnetic resonance imaging
|Magnetic resonance imaging (MRI) is evolving as the most important technique for evaluating the size and functioning of the right ventricle. An MRI machine uses a magnetic field to produce a detailed image of the scanned area of the body. It is especially useful in viewing soft tissues as it provides greater contrast than techniques such as x-ray.
|MRI’s are important in assessing pulmonary valve competence and the severity of regurgitation (the amount of blood that flows back into the right ventricle due to the incomplete closure of the pulmonary valves) in patients with TOF. It can measure the volume and mass of the right and left ventricles and can assess the degree of pulmonary outflow tract obstruction. Finally, MRIs are important in measuring the degree of ventricular septal defect. (Somerville, 1993)
|Insert MRI image here
|-
|}

Hey peeps just put a intro just as a draft...tell me what you guys think of it. Edit it as you may wish.... And Jaq, if you describe briefly how each test works it would be good, regards --[[User:Z3291317|Z3291317]] 23:16, 14 September 2011 (EST)

hey jaz, ive fixed up the diagnosis, but feel free to add anything! or let me know if you think i should add anything. --[[User:Z3291324|z3291324]] 10:06, 14 September 2011 (EST) should i describe each diagnostic test!!??--[[User:Z3291324|z3291324]] 10:07, 14 September 2011 (EST)

Hey Guys! just added a very few changes, links etc to treatment. I've begun to add make a bit of notes on diagnosis that could just add a bit of detail to the diagnosis section. just wondered if any of you guys know what particular section of the ECG indicates...Left Ventricular Hypertrophy etc maybe ill call up a cardiologist :P nonetheless ill add references and some things to diagnosis tmrw night. regards, --[[User:Z3291423|z3291423]] 00:15, 14 September 2011 (EST)

Hey jaq. no particular order, the referencing system in the wiki automatically arranges it according to the order it is found in the text. In text referencing is NEEDED, lol. Type in the text title into Pubmed and when the article is found, the pmid code will be found at the bottom of the abstract for that article. if you cant figure out how to reference, put in the pubmed ids as intext citations then ill fix it for you...Make pathophys a bit more simpler, but do not compromise the anatomical words, i.e. write the anatomical word, then write in brackets what it means, eg. ''...anterolaterally (at the top away from the midline)'' is just an example (a crap one to lol). Also did you find any new info for diagnostic tests? and Rom, why did you remove info from the 22q section???? regards --[[User:Z3291317|Z3291317]] 22:02, 13 September 2011 (EST)

hey guys, quick question about the referencing. are they in any particular order? or should i just add mine to the end of the list? and do we need to do in-text referencing?? and how do you find the pmid code? also, any suggestions on how i should improve pathophys? ie make it more anatomical based or reword it so its simpler? thanks --[[User:Z3291324|z3291324]] 21:30, 13 September 2011 (EST)

Hey Rom, looking good thus far. if you need help with referencing even after trying so much i can help you during the 1 hour we have afta the lecture tomorrow to go through and help you fix em up... its a bit tricky but can get a handle of it... --[[User:Z3291317|Z3291317]] 20:37, 12 September 2011 (EST)

Hey guys sorry for the delay, but I'm slowly uploading all my stuff up. I'm just a bit confused about how I do the reference tag thing, as you can see there is a massive red thing on our reference list. I tried copying how you guys did it but I failed at it. I'll be posting some more in the next couple of hours, I just need to get a hang of this coding thing gah!
--[[User:Z3290841|z3290841]] 19:36, 12 September 2011 (EST)

hey rommel, we really need to see your part of the project and get your suggestions on parts we have done because its due on thursday --[[User:Z3291324|z3291324]] 19:16, 12 September 2011 (EST)

Hey Peeps, Just reconstucted the referencing so they are done exactly as it should be... Also just uploaded a pic of Mr fallot Himself without any copyright restrictions ( aha ow ye ow ye, took me long before i found it lol). I left the intext references jac and jaz put in their sections for future reference. Thats about it for now... Jaz i hope u liked the pics i showed you, and i hope rom is going well in his section... See yous soon... Regards --[[User:Z3291317|Z3291317]] 17:36, 11 September 2011 (EST)

update: uploaded the drawn images, took ages but its finally done :) and I've just finished the future directions :) so it should be fine to edit and look over in the next couple of days!
regards --[[User:Z3291423|z3291423]] 13:16, 11 September 2011 (EST)

looking good jaz. thanks for the articles fru. ive had a quick look at them but will need to fix it up after work this arvo! --[[User:Z3291324|z3291324]] 11:59, 11 September 2011 (EST)

Hey Jac, ive got 2 articles that i will send to your email, both talk about Cardiac Magnetic Resonance, one some detail about electrocardiography. Also, Jaz i have an article that has a section based on 'Future Innovations' for TOF, have a read and i reckon it will help out with the future directions part... i will send these articles to your emails so look at them when yous can... and rom, you breathing my friend?... regards --[[User:Z3291317|Z3291317]] 01:29, 11 September 2011 (EST)

hey guys, just reworded diagnosis so it makes sense. can anyone suggest any good articles to read for diagnosis? im having trouble accessing a lot of articles (they keep asking for passwords) and a lot of the articles dont discuss diagnosis in much detail at all. help is much appreciated!! thanks :) --[[User:Z3291324|z3291324]] 21:12, 10 September 2011 (EST)

hey rom, this might be helpful for genetics. not sure what youve got already though http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747103/
--[[User:Z3291324|z3291324]] 20:50, 10 September 2011 (EST)

also what should i do about the symptoms-pathophys overlap. should i alter the pathophys so its more anatomical like in the below article??--[[User:Z3291324|z3291324]] 20:10, 10 September 2011 (EST)

On to it now fru. thanks for the article. should i reword pathophys too so its easier to read/understand?--[[User:Z3291324|z3291324]] 20:08, 10 September 2011 (EST)

Hey Fru: in regards to the below comments, im working on future directions now :) also i read through the history section and it seems a lot more better :) just one mistake is the
"durng such operations there need". Ill have my edited prognosis and futures up by tonight! :) ohh and the heart! regards --[[User:Z3291423|z3291423]] 11:03, 10 September 2011 (EST)

Hey Jac i was reading the article: Review - Tetralogy of Fallot by Frederique Bailliard and Robert H Anderson ( im sure you have this one) and theres a section absed on " Anatomical variants of Tetralogy of Fallot, and associated anomalies". i believe if you could also include this section into the Pathophysiology section it would be great! Furthermore would you please do the things Mark said in regards to your sections it would be good, especially the diagnostic tests part :). Also to everyone we need to get Future Directions and especially Genetics up ASAP! thus respective people have them completed asap. --[[User:Z3291317|Z3291317]] 22:49, 9 September 2011 (EST)

Hey jaz, the prognosis sounds pretty good. maybe expand/explain how the hypoxic spells, brain abscesses etc cause death. i think in general we could expand upon most sections. off to work now guys but ill fix up my couple of sections tonight/tomorrow morn! --[[User:Z3291324|z3291324]] 08:30, 9 September 2011 (EST)

Thanks Fru! I will definitely crack onto those suggestions, I'm going to first email the owner of the children's hospital video on youtube to get permission for using the video, and then ill put it up in my section.
ALSO, I've nearly done the picture! I've got an outline and as your reading this, i should have it coloured, labelled and ready for upload! :D

have a great weekend guys!

Reagards
--[[User:Z3291423|z3291423]] 23:29, 8 September 2011 (EST)

Hey jaz just read your prognosis section. You made it well, however,i picked up 2 things you could do and it woould be good if you do them: 1. The causes of death after no surgery has done; if you can explain how these 'causes of death' occur due to TOF, it will portray the role TOF has in these problems. 2. You should talk about any complications that could arise in both patients that dont have corrected TOF and the ones who do have the surgery (i.e. any conditions that could develop after having the surgery or not, not just the death of the patient if they dont correct their heart). Other than that great work! :) --[[User:Z3291317|Z3291317]] 23:17, 8 September 2011 (EST)

Ye Jaz, thanks for the pic. Aswell ive attached a reviewed file of the treatment section on an email i sent to you. Maybe the youtube cideo based on the TOF fix up can now be put under this section as an embedded video... --[[User:Z3291317|Z3291317]] 22:19, 8 September 2011 (EST)

hey jaz, the treatment section is much better, much easier to read. thanks for the heart pic! im pretty sure my section is he one that is too "verbose" so anyone feel free to fix it up--[[User:Z3291324|z3291324]] 19:47, 8 September 2011 (EST)

Hey Guys! sorry prognosis took me a bit longer to do, but It will be up by tonight :) and ill upload the heart pic as well :) which took forever to make!
regards --[[User:Z3291423|z3291423]] 16:05, 8 September 2011 (EST)

hey guys just put up some diagnosis, let me know if you want me to add anything to it. furkan, glossary looks good! rommel, how are you going with the genetics do you need any help? and jaz are you able to post up the prognosis? once they are all up we should go through and edit them all together and fix up the wording. --[[User:Z3291324|z3291324]] 15:50, 8 September 2011 (EST)

Hey peoples...im going to start constucting the glossary wordbank as i read the entire document. Please add words yous think i missed out on... Also i found a pic of Mr Fallot but i think theres copyright rights on it. i think i gotta clear it somehow...--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

hey jaz, i think the treamtment section is alright. maybe reword the first bit into sentences (i think it was the bit on how severe the cyanosis is) so its a bit clearer. but otherwise good :) what do you think about pathophys?--[[User:Z3291324|z3291324]] 12:40, 7 September 2011 (EST)

hey guys, i cant tell if this pic has copyright or not. can someone please have a look for me? http://www.nhlbi.nih.gov/health/health-topics/topics/tof/ thanks!--[[User:Z3291324|z3291324]] 09:49, 6 September 2011 (EST)
--> REPLY: I looked at the pic and looks great. however, i couldnt see if it was copyright or not. HOWEVER, it is found on a public government website, and from what i remember Mark said we can use these materials. To make sure just please check it with him aswell. Also, im going to format your pathophysioligy section now so it looks prettier :)--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

Hey guys, i Just finished the Treatment part, I've got palliative in this heading to still complete but Its very brief so i thought id get cracking on getting that drawing done and also the prognosis will be up by tomorrow! also check this out! http://www.nemours.org/content/dam/nemours/www/filebox/service/medical/cardiology/defect/tof.swf
--[[User:Z3291423|z3291423]] 23:57, 5 September 2011 (EST)
-->REPLY: Cool animation. Would we use an external link to this animation due to copyright restrictions?--[[User:Z3291317|Z3291317]] 19:19, 7 September 2011 (EST)

Hey Peepz

I just finished the sections of History, Signs and symptoms and Epidemiology

just please check these sections, especially the epidemiology one, do yous want it more detailed or is it enough?

z3291324 your section seems alright so far, show us your edited version so we can fully critic it then.

p.s. the post below my one i dont really understand itl who is speking to who and what are yous refering to? lol

Regards --[[User:Z3291317|Z3291317]] 23:44, 4 September 2011 (EST)

j: the article on future treatment directions sounds good. i might add some of the info in to the pathophysiology section because it links in well with the pulmonary stenosis and right ventricular hypertrophy. --[[User:Z3291324|z3291324]] 13:47, 2 September 2011 (EST)
I think this article makes some good points which could be added into the treatment section (eg discuss treatment/surgery after birth and also follow up treatments in adulthood- pulmonary valve replacement etc due to valvular incompetence and regurgitation because of the growing heart)

=pathophysiology=
hey guys. ive written some basic notes (UNEDITED) for pathophysiology. Just want to get an idea of how much detail i should go into before i start adding links to journal articles etc. can someone please have a quick look through and give me an idea of how much more detail is needed. thanks :)

The four features of tetralogy of fallot are pulmonary stenosis, overriding aorta, ventricular spetal defect and right ventricular hypertrophy. These features result from the anterosuperior displacement of the infundibular septum. The severity of symtpoms is determined by the extent of right ventricular outflow obstruction. 
'''Pulmonary stenosis'''
(Symptoms include cyanosis, right ventricular hypertrophy, hepatomegaly and peripheral oedema (of the legs). More mild symptoms include sudden fainting and dizziness from exercise. ) 
Valvular or infundibular stenosis (narrowing of the outflow tract of the right ventricle). Obstructs the outflow of blood from the right ventricle reducing pulmonary flow. If the pulmonary stenosis is mild, a left to right shunt (with no cyanosis) will form, due to the higher pressure in the left ventricle. However, significant pulmonary stenosis can raise right ventricular pressure above the left ventricular pressure and cause a right to left shunt (cyanosis etc). The pathophysiology of pulmonary stenosis usually worsens with age because the pulmonary orifice stays the same size despite an increase in the size of the heart. 
'''Overriding aorta'''
The aortic valve has a biventricular connection. Instead of being positioned over the left ventricle, the aortic valve is located above the interventricular spetal defect allowing blood from both the right and left ventricles to pass through the aortic valve. The degree to which the overriding aorta is continuous with the right ventricle determines the severity of symptoms. Because the right ventricle receieves deoxygenated blood from the systemic circulation, the percent oxygenation of bloood entering the aorta and hence back into the systemic circulation is decreased. 
'''Ventricular septal defect'''
The interventricular septum dividing the left and right ventricles is incomplete at its superior, membranous end. During ventricular contraction, blood from the left ventricle passes into the right ventricle and then re-enters the pulmonary circulation. Leakage of blood from the left to right ventricle raises the right ventricular volume and pressure resulting in pulmonary hypertension. (Shortness of breath, dizziness and fainting) If the right ventricular pressure exceeds that of the left, the left to right shunt is reversed and the patient will experience cyanosis and deoxygenated blood is by-passing the lungs and entring the systemic circulation. (also breathlessness, poor feeding and failure to thrive in infancy.) 
'''Rigth ventricular hypertrophy'''
Compensatory response to pulmonary stenosis ...to be contined.

--[[User:Z3291324|z3291324]] 13:38, 2 September 2011 (EST)

=link to pathology textbook=

hey guys, this is the link to tetralogy of fallot in robbins pathology
--[[User:Z3291324|z3291324]] 13:05, 2 September 2011 (EST)

=More genetics and Surgery=

Hey Peeps, i forund another article in regards to Genetics as it does an genotype-phenotype anaylis os TOF Patients. Have a read and see if it can help in the assignment subsection. if you cant get the full article tell me and ill give you the pdf of it.

Article: PMID: 19948535

And Regards to surgery and its prognosis post-operation i found these articles that may be helpful for 3291423. Again if yous cant find the pdf tell me and i'll send yous the pdf articles of these.

Articles: PMID: 20091166 ; PMID: 21769263 ; PMID: 21566339 (hey 3291423 this is the article i showed you in the lab and you wanted it from me)

Anyways peeps i hope all the assignments are coming along well

Regards --[[User:Z3291317|Z3291317]] 19:03, 1 September 2011 (EST)

REPLY: Thanks z3291317, I had a look through the files and am using them now for summarising :) also, can you send through the picture of what you want the abnormal TOF heart to look like and ill get cracking on it to produce/draw it :)

regards --[[User:Z3291423|z3291423]] 22:15, 1 September 2011 (EST)

=Genetics=
Hey guys, found some articles relating to genetics and the deletion of the 22q11 gene. take a look :)
--[[User:Z3291423|z3291423]] 21:09, 27 August 2011 (EST)

AS Bassett, EWC Chow and J Husted et al., Clinical features of 78 adults with 22q11 deletion syndrome, Am J Med Genet 138 (2005), pp. 307–313. http://pediatrics.aappublications.org.wwwproxy0.library.unsw.edu.au/content/112/1/101

http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science?_ob=MiamiImageURL&_imagekey=B6T18-3V8RDDJ-11-1&_cdi=4884&_user=37161&_pii=S0735109798002599&_check=y&_origin=&_coverDate=08%2F31%2F1998&view=c&wchp=dGLbVlW-zSkWz&md5=0a4f32c3b75ebff2513309081ac0468f&ie=/sdarticle.pdf

http://pediatrics.aappublications.org.wwwproxy0.library.unsw.edu.au/content/112/1/101

=Treatment and future directions info/readings=

Hey guys, found this really amazing article about treatments and their repercussions http://www.ccjm.org/content/77/11/821.long#abstract-3
--[[User:Z3291423|z3291423]] 21:09, 27 August 2011 (EST)

=Online lab 4 info=
I my friends , colleagues and countrymen am going to be undertaking the research of the subsection Genetics/Aetiology in the topics that have been discussed. --[[User:Z3290841|z3290841]] 10:18, 25 August 2011 (EST)

Im going to be researching Treatment/Management, Prognosis & Future directions. - z3291423

regards, --[[User:Z3291423|z3291423]] 23:30, 24 August 2011 (EST)

Thanks for typing them up. I'm going to research Pathophysiology and abnormalities and diagnostic tests.
--[[User:Z3291324|z3291324]] 15:40, 24 August 2011 (EST)

Hey Group 6

From the Meeting on Tuesday after the Embryo lecture, we had concluded that we are going to divide the group project of TOF into the following sub-sections (if i am not mistaken):

* Introduction
* History
* Epidemiology
* Signs and Symptoms
* Genetics/Aetiology
* Pathopgysiology and Abnormalities
* Diagnostic Tests
* Treatment/Management
* Prognosis
* Future Directions
* Glossary
* References

From these subsections, I (z3291317) will research the History, Epidemiology and Signs & Symptoms subsections of the group Project.

Just wanted to put forward my part for the group project :)

Regards --[[User:Z3291317|Z3291317]] 15:01, 24 August 2011 (EST)

=Resources=
Hey Group 6

When i was looking around for info in regards to TOF, i found some videos on youtube made by an american hospital which we could use on our page in the "more info" section. Check them out and tell me what yous think...

- http://www.youtube.com/watch?v=ACRfFkxow7w
- http://www.youtube.com/watch?v=jgLC2QABcxo

So what you guys think? --[[User:Z3291317|Z3291317]] 22:54, 21 August 2011 (EST)

COMMENT: great stuff! that really is a great tool, maybe we can incorporate that in as a link, or something to really explain it! without all the mumbo jumbo :) --[[User:Z3291423|z3291423]] 22:22, 22 August 2011 (EST)

=Articles=

Found really good article detailing some clinical aspects http://journals.cambridge.org.wwwproxy0.library.unsw.edu.au/action/displayAbstract?fromPage=online&aid=331031 its called: The clinical anatomy of tetralogy of Fallot, http://www.sciencedirect.com.wwwproxy0.library.unsw.edu.au/science/article/pii/S0140673609606577 - Tetraology of ballot by christian apitz, just google scholar it via unsw or use the link I've given you :) --[[User:Z3291423|z3291423]] 19:10, 20 August 2011 (EST)

=Images=
Hey guys, this is an image of tetralogy of fallot with pulmonary atresia

[[File: Tetralogy of Fallot with pulmonary atresia.jpg]]
--[[User:Z3291324|z3291324]] 22:07, 17 August 2011 (EST)

Hey guys, just found this still frame showing large ventricular septal defect, aortic override, and right ventricular hypertrophy which are all very common to patients with ToF
[[File:Some common effects for patients with Tetralogy of Fallot.jpg]]
--[[User:Z3291423|z3291423]] 21:43, 17 August 2011 (EST)

Hey guys this is my image of our disease, it is just outlining some of the basic changes that happens to the heart, mainly the right ventricle.

[[File:Right ventricle of heart with Tetralogy of Fallot.jpg]]

--[[User:Z3290841|z3290841]] 13:42, 17 August 2011 (EST)

----

Hey Group 6, its z3291317

I just wanted to make it clear that we add all new entries into our discussion page at the top of the page and not at the bottom of it. Thats how we are told to edit this discussion page.

Anyways this is my Image for Lab 3 Question 2:

[[File:Normal fetal blood flow and Tetralogy of Fallot.jpg]]

I hope it would be beneficial for our page...

--[[User:Z3291317|Z3291317]] 12:05, 17 August 2011 (EST)

--[[User:Z3291317|Z3291317]] 17:00, 7 August 2011 (EST)
Hey Group 6

i just done some research on a possible group project subject. It is quite detailed and interesting (to me) disease to write on.What do you guys think? Here is the review and research article for it:

The Disease:'''Tetralogy of Fallot'''

Review Article:

Orphanet J Rare Dis. 2009 Jan 13;4:2.

'''''Tetralogy of Fallot.'''''

Bailliard F, Anderson RH.

North Carolina Children's Heart Center, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. frederique_bailliard@med.unc.edu

Link: <ref><pubmed>19144126</pubmed></ref>

Description: This paper gives an overview about the disease, how it happens, and clinical manifestations.

Research Article:

J Med Genet. 2010 May;47(5):321-31. Epub 2009 Nov 30.

'''''Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.'''''

Rauch R, Hofbeck M, Zweier C, Koch A, Zink S, Trautmann U, Hoyer J, Kaulitz R, Singer H, Rauch A.

Institute of Medical Genetics, Schorenstrasse 16, CH-8603 Zurich-Schwerzenbach, Switzerland. anita.rauch@medgen.uzh.ch

Link: <ref><pubmed>19948535</pubmed></ref>

Description: A study was done to see the prevalent phenotype for Tetralogy of fallot, and it was found that the 22q11.2 deletion was the most common type in Tetralogy of Fallot.

'''''References:'''''

<references/>

--[[User:Z3291317|Z3291317]] 17:00, 7 August 2011 (EST)

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--[[User:Z3290841|z3290841]] 09:36, 8 August 2011 (EST)

Hey Guys,

I did research on Cystic fibrosis and these are the 2 articles that I found that explains a lot about the disease, and the genetic research on it.

Review Article:

'''Cystic Fibrosis: Seminar'''

Description: This is basically outlining the pathophysiology of the disease, disease manifestation,current treatments diagnostic tool.

Ratjen F & Doring G.(2003).Cystic Fibrosis: Seminar.''The Lancet'', 361, 681-9. Retrieved from http://www.sciencedirect.com/science/article/pii/S0140673603125676

Research Article:

'''Gene expression profile study in CFTR mutated bronchial cell lines'''

Description: This article provides information about the severity of gene expression in relation of the extent or type of mutation.

Gambardella S, Biancolella M, D'Apice M, Amati F, Sangiuolo F, Farcomenti A, Chillemi G, Bueno S, Desideri A & Novelli G.(2006).Gene expression profile study in CFTR mutated bronchial cell lines.''Clinical and Experimental Medicine '', 6, 157-65. Retrieved from http://proquest.umi.com/pqdlink?Ver=1&Exp=08-05-2016&FMT=7&DID=1187181501&RQT=309&cfc=1

--[[User:Z3290841|z3290841]] 09:36, 8 August 2011 (EST)

--[[User:Z3291324|z3291324]] 20:48, 10 August 2011 (EST)

Hey guys, I like the disease that Furkan found (tetralogy of fallot)! What does everyone think?

These are the two articles I found. The review article gives a pretty good description of the disease, symptoms, treatment and complications etc. The research article looks at some of the genetic causes.

Goldmuntz, E., Geiger, E., & Benson, D. W. (2001). NKX2.5 mutations in patients with tetralogy of fallot. Circulation, 104(21), 2565-2568.

Apitz, C., Webb, G. D., & Redington, A. N. (2009). Tetralogy of Fallot. Lancet, 374(9699), 1462-1471.

Hey kiddes just done some research! check it out, its about Hypoplastic left heart syndrome

Review article:

2001 May-Jun;21(3):705-17.
'''Hypoplastic left heart syndrome.'''
Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP.

Link: [http://www.ncbi.nlm.nih.gov/pubmed/11353117]

Research:

2011 Aug 1;108(3):421-7. Epub 2011 May 31.
'''Prenatal diagnosis of hypoplastic left heart syndrome in current era.'''
Kipps AK, Feuille C, Azakie A, Hoffman JI, Tabbutt S, Brook MM, Moon-Grady AJ.
Link: [http://www.ncbi.nlm.nih.gov/pubmed/21624547]

References
<references/>
1. Bardo DM, Frankel DG, Applegate KE, Murphy DJ, Saneto RP ""Hypoplastic left heart syndrome.""Radiographics. 2001 May-Jun;21(3):705-17 <ref><pubmed>11353117</pubmed></ref>

2. Kipps AK, Feuille C, Azakie A, Hoffman JI, Tabbutt S, Brook MM, Moon-Grady AJ ""Prenatal diagnosis of hypoplastic left heart syndrome in current era."" Am J Cardiol. 2011 Aug 1;108(3):421-7. Epub 2011 May 31 <ref><pubmed>21624547</pubmed></ref>

==Peer Assessments==
* I would suggest placing the history section into a timeline or table format just so that significant dates are more clear and emphasised.
* The gene profile section was great. It was in detail, it was coherent and the inclusion of gene images enhanced my understanding of this particular section.
* Maybe for the “how the procedure works” section of the diagnostics table could have been summarised into a flow diagram or through images, rather than having a chunk of text. This could make it more straight forward to the reader.
* Your website was generally well-written and to the point. You varied your formatting regularly which made your page entertaining.
* My last suggestion would to only use the image of the shunt once and finding a different image as the repetitiveness of this is slightly disengaging
--[[User:Z3332629|z3332629]] 15:26, 22 September 2011 (EST)

Talk:2011 Group Project 6

2011-10-12T11:43:02Z

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