2011 Group Project 6

From Embryology
Note - This page is an undergraduate science embryology student group project 2011.
2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip

Tetralogy of Fallot

--Mark Hill 15:50, 8 September 2011 (EST) This has reasonable sub-heading structure, but several sections still lack any content, which they should by now. There are only 2 figures and the text in places is verbose, and very poorly structured for ease of reading/understanding.

  • Introduction - No text here? This is where the reader starts and it should grab their attention to your topic.
  • History - Good early background. Quoted text should be indented. You have included only a few time points in the disease up to 1945-50's and only broadly thereafter. The text is also very clinically technical, suggesting that you have just copied without understanding the content itself.
  • Signs and Symptoms - this should have subsections for each description.
  • Genetics/Aetiology - No text here?
  • Pathophysiology and Abnormalities - Seems to overlap with the Signs and Symptoms content.
  • Diagnostic Tests - you name the tests but do not describe how they work or what they show, this could easily be illustrated.
  • Treatment/Management - I think this should be far better structured in layout and content.
  • Prognosis - No text here?
  • Future Directions - No text here?


'Blue babies' is the name given to infants of this disease. Infants turning blue when crying, children collapsing due to tet spells during exercise, patients easily feeling fatigued. These are the experiences by Tetralogy of Fallot (TOF) patients.

TOF is a congential heart disease that is believed to be caused by a genetic mutation. Studies show that the TOF occurance is 3 in 10000 live births delivered. TOF is a disease which causes its problems once the infant has been born. Furthermore, it is believed that the genetic aetiology of tof is a mutation in one of the following chromosomes: 5, 20 and 22. This causes the heart to be that of tof, and thus results in the following cardiac abnormalities:

  • Pulmonary stenosis
  • Overiding aorta
  • Ventricular septal defect
  • Right ventricular hypertrophy

During the development of the understanding of the TOF disease, key historical figures Etienne Fallot, Helen Taussig and Alfred Blalock played major roles in identifying this abnormality and determining how to treat it. This lead to acknowledging that the only way to completely treat TOF is surgery, even though there are medical therapy and palliative procedures for TOF. It should be mentioned that having the corrective surgery increases the survival rate of TOF patients. Furthermore, current research is directed into areas of percutaneous pulmonary valve replacement, Genetic Mutation and therapy, oral drug therapy and in vitro engineered valves for possible ways to treat TOF.


Early History

Portraight 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[1] :

“…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”[1]

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[1].

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.[2]

Portraight 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[2].

It was in the morning of 1943 in which 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. 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.[2]

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[2].

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 [2].

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[1]. In retrospective studies it shows how surgical procedures have improved. From the 1950’s till today, the mortality rate from surgery dropped from 50% to less than 2%[3].

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[3].

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[4].


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 then females.[5]

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.[6]

Signs and Symptoms


The most important sign of TOF patients is Cyanosis. This is when the lips, fingernails and skin of the patient turns into a bluish colour[7]. It is considered to occur due to decreased amounts of oxygenated haemoglobin found within the blood when cyamnosis occurs [8].

Tet Spells and Fatigue

Babies who have TOF can at times enter into ‘tet spells’, in which there is a sudden drop in Oxygen saturation of the blood, causing the baby to turn blue. These tets spells become apparent when the baby does certain activities such as crying[9]. An image portraying tet spell in an infant can be found here: Cyanotic 'Tet spell'

In addition to the 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.[10]

Heart Murmur

Another common sign of TOF is heart murmur 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[11]. 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: First and Second Heart Sounds - Normal & Unsplit - Waveform and Audio -- TOF Heart:Tetralogy of Fallot - Waveform and Audio

The types of murmurs that can be present in the heart include [4]:

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 [4].

Abnormal Growth

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 [12].

An example of Finger Clubbing


TOF children may also have clubbing. [13] This clubbing would be evident as there would be enlargenemt of the bone or the skin around the fingernails of the patient. [14]

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.[4]


--Mark Hill 16:05, 8 September 2011 (EST) No text here?

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.


  • Gene affected = TBX1
    • Description:
      • Location[15]:
        • Chromosome number = 22
        • Chromosomal arm = q (long arm)
        • Position on the chromosome = 11.21
        • Base pair region = 19,744,225 to 19,771,115
      • This gene is responsible for the production of T-box 1 protein, which is a transcription factor.
      • TBX1 protein is dose sensitive. This means that the amount of protein produced by the gene is reduced once there is increased amount of the transcription factor.
      • It contributes to the development of the outflow tract and right ventricle of the heart. This is by regulating the expression of the genes via the binding of the protein to specific area in the DNA.[16]
      • Unfortunately the genes regulated by this protein are still not well known, even though its mechanism and function have already been determined.
    • Genetic abnormality and result
      • Microdeletion of 3 or 1.5 Mb of 22q11.2 region on chromosome 22 according to Rauch et al. [17] is the most common mutational anomaly in patients with TOF. They also mentioned that the result of these microdeletions 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, as a single copy of the gene is incapable of producing enough protein that will allow normal function.[18]
      • Rauch et al.[17] explained one variation of mutation that they have observed in one patient that expressed non-syndromic TOF. The data showed a heterozygous 30-bp duplication in exon 9c of the TBX1 gene of patients with TOF. This leads to the production of non-functioning TBX1 protein because the insertion of the duplicate leads to the expansion of the polyalanine tract. The proteins produced aggregates within the cytoplasm, leading to decrease in transcription of Tbx1 gene, since this gene is dose-dependent. Also the proteins produced are non-functioning, thus transcription of genes that the T-box 1 protein is responsible for is not initiated.
    • Involvement with Tetralogy of Fallot
      • Studies have shown 74% of patients with 22q11.2 microdeletions have Congenital Heart Defect, and out of these 22% have Tetralogy of Fallot.[19]
    • Other phenotype of the mutation:
      • DiGeorge Syndrome
      • Velocardiofacial Syndrome
      • Conotruncal anomaly face syndrome


  • Gene affected = NKX2-5
    • Description:
      • Location[20]:
        • Chromosome number = 5
        • Chromosomal arm = q (long arm)
        • Position on the chromosome = 34
        • Base pair region = 172,659,106 to 172,662,314
      • Encodes the NK2 homeobox 5, which is a transcription factor.
      • NK2 homeobox 5 is essential in tissue differentiation and temporal and spatial patterns of development in cardiac tissue.[21]
      • This protein is particularly involved in the development of atrial, ventricular and conotruncal septation, AV conduction and AV valve formation[22] .
    • Genetic abnormality and result
      • Goldmuntz et al[23] suggested 3 substitution mutation of the NKX2.5 gene for patients with TOF resulting in right-sided aortic arch, mirror-image aortic arch branching, and a retroaortic innominate vein. This includes:
        • glu-to-gln at codon 21 position
        • arg-to cys at codon 216 position
        • ala-to val at codon 219 position
    • Involvement with Tetralogy of Fallot
      • Goldmuntz et al[23] found at least 4% of TOF patients in the study they conducted have NKX2.5 mutation. Patients with this mutation are also found to be non-syndromic TOF patients.
    • Other phenotype of the mutation:
      • Hypothyroidism
      • Congenital nengoitrous
      • Atrial septal defect with atrioventricular conduction defects


  • Gene affected = JAG1
    • Description:
      • Location[24]:
        • Chromosome number = 20
        • Chromosomal arm = p (short arm)
        • Position on the chromosome = 12.1 to 11.23
        • Base pair region = 10,618,331 to 10,654,693
      • The gene is composed of about 36 kb with 26 exons[25]
      • The gene expresses Jagged-1 protein, which is a ligand of the Notch receptor[26].
      • JAG1 Gene is highly expressed in developing mammalian heart, thus Jagged-1 ligands are present on cardiac cell membranes<pubmed>10556292</pubmed></ref>.
      • With the Notch receptor present on adjacent cells, Jagged-1 protein is involved in intercellular signalling between adjacent cells. This is because ligand-receptor bond leads to the release of the receptor’s intracellular region from the membrane. This part is transported into the nucleus activating transcription factors that affects cellular function, leading to cell differentiation and morphogenesis.[27]
    • Genetic abnormality and result
      • There is a missesnse mutation of the JAG1 gene (G274D), which is gly-to-asp 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.[28]
      • There are 2 types of proteins resulting from the mutation of the allele with the abnormal functioning protein produced at higher temperature[29]:
        • Abnormally glycosylated Jagged-1protein that was retained intracellularly and not transported to cell surface
        • Normally glycosylated protein that retains its function as a ligand to NOTCH receptor, as it is transported to the cell surface
      • The result is the development of traits that are characteristic of TOF, including ventricular septal defect with aortic dextroposition and isolated pulmonic stenosis.[28]
    • Involvement with Tetralogy of Fallot
      • The typical clinical presentation of mutation in this gene is a disease called Alagille Syndrome (AGS) which have some clinical overlap with that of TOF, which are mainly right heart abnormalities.[30]
    • Other phenotype of the mutation:
      • Alagille Syndrome
      • Deafness
      • Congenital heart defects
      • Posterior embryotoxon

Pathophysiology and Abnormalities

The four pathological features of tetralogy of fallot are:

  1. Pulmonary stenosis
  2. Overriding aorta
  3. Ventricular septal defect
  4. Right ventricular hypertrophy
Tetralogy of fallot-the 4 defects

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.

1. Pulmonary stenosis - Pulmonary stenosis may be caused by a narrowing of the pulmonary valve (valvular stenosis) or the outflow tract of the right ventricle (infundibular stenosis). 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. 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 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.

2. Overriding aorta - Instead of being positioned directly over the left ventricle, the aorta is displaced anterosuperiorly. 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. 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.

Normal fetal blood flow and Tetralogy of Fallot

3. 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 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 hypertension and right ventricular 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 cyanosis because deoxygenated blood is bypassing the lungs and entering the systemic circulation.

4, Right ventricular hypertrophy - Hypertrophy of the right ventricle is a compensatory response to pulmonary stenosis. Because the pulmonary outflow tract is narrowed, the right ventricle must pump harder to meet the oxygen demands of the body.

Due to such pathological features in Tetralogy of Fallot, the diagram on the right shows the blood flow in a normal and Tetralogy of Fallot heart.

Diagnostic Tests

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)

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


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)

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)


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)

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)

Apitz, C., Webb, G. D., & Redington, A. N. (2009). Tetralogy of Fallot. Lancet, 374(9699), 1462-1471. Bailliard, F., & Anderson, R. H. (2009). Tetralogy of Fallot. Orphanet J Rare Dis, 4, 2. Somerville, J. (1993). Congenital heart disease in the adult: problems for the adult cardiologist. Schweiz Med Wochenschr, 123(43), 2056-2059.


The treatment for TOF consists of medical therapy, surgery & palliative procedures.

Medical therapy:

Medical therapy is usually used to prepare the infant/adult for surgery. The degree of therapy and what is used for treatment, depends upon the degree of cyanosis found in the patient.

  • Patients with acute cyanosis usually carry out knee to chest exercise positions in order to decrease the amount of deoxygenated blood entering circulation. This along with providing oxygen & intravenous morphine to provides more blood flow to the lungs and also decrease ventilator drive. Cite error: Closing </ref> missing for <ref> tag, which are involved in cardiogenesis, 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) [Clinical application of tissue engineered human heart valves using autologous progenitor cells. PMID: 16820562][31]. 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. [Joanne P Starr Tetralogy of fallot: yesterday and today. World J Surg: 2010, 34(4);658-68 PMID:20091166][5].


Annular hypoplasia – (need definition)

Arrythmia - (dysrhythmia) Term refers to cardiac abnormality of heartbeat either fast, slow, or irregular.

Ascites – term refers to when there is excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity).

Clubbing – term refers to changes in the areas under and around the toenails and fingernails, and in the nails themselves that may occur with some disorders

Cyanosis - Clinical term referring to a blue coloration of the skin and mucous membranes due to the presence of deoxygenated hemoglobin. Can be due to several different causes including 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 – term refers to Shortness of breath, difficult or laboured breathing

Edema/Oedema - term for 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 – term refers to swelling of the liver beyond its normal size

Murmur – term refers to 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

Palpitation – term refers to unusually or abnormally rapid or violent beating of the heart

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

Stenosis - Term used to describe an abnormal narrowing, usually in relation to a tube. For example, blood vessel, gastrointestinal tract or respiratory tract.

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


  1. 1.0 1.1 1.2 1.3 <pubmed>19683809</pubmed>
  2. 2.0 2.1 2.2 2.3 2.4 <pubmed>7888802</pubmed>
  3. 3.0 3.1 <pubmed>21251297</pubmed>
  4. 4.0 4.1 4.2 4.3 <pubmed>21048055</pubmed>
  5. 5.0 5.1 <pubmed>20091166</pubmed>
  6. <pubmed>19853711</pubmed>
  7. http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html
  8. http://www.ncbi.nlm.nih.gov/books/NBK367/
  9. http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html
  10. http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html
  11. http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html
  12. http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html
  13. http://www.nhlbi.nih.gov/health/health-topics/topics/tof/signs.html
  14. http://www.nlm.nih.gov/medlineplus/ency/article/001567.htm
  15. http://ghr.nlm.nih.gov/gene/TBX1
  16. <pubmed>20937753</pubmed>
  17. 17.0 17.1 <pubmed>19948535</pubmed>
  18. http://ghr.nlm.nih.gov/glossary=haploinsufficiency
  19. <pubmed>11339373</pubmed>
  20. http://ghr.nlm.nih.gov/gene/NKX2-5
  21. <pubmed>7665173</pubmed>
  22. <pubmed>10587520</pubmed>
  23. 23.0 23.1 <pubmed>1714651</pubmed>
  24. http://ghr.nlm.nih.gov/gene/JAG1
  25. <pubmed>9268641</pubmed>
  26. <pubmed>11869892</pubmed>
  27. Cite error: Invalid <ref> tag; no text was provided for refs named PMID11869892
  28. 28.0 28.1 <pubmed>11152664</pubmed>
  29. <pubmed>12649809</pubmed>
  30. <pubmed>12427653</pubmed>
  31. <pubmed>16820562</pubmed>

2011 Projects: Turner Syndrome | DiGeorge Syndrome | Klinefelter's Syndrome | Huntington's Disease | Fragile X Syndrome | Tetralogy of Fallot | Angelman Syndrome | Friedreich's Ataxia | Williams-Beuren Syndrome | Duchenne Muscular Dystrolphy | Cleft Palate and Lip