Tetralogy of Fallot
Update September 27, 2020
Little is known about the exact etiology of Tetralogy of Fasllot.
There is a well-accepted association between certain genetic defects and congenital heart disease.
Patients with trisomy 21, 18, or 13 have a higher incidence of TOF than infants without trisomy. [4] A retrospective analysis in patients with apparently nonsyndromic TOF found 10 out of 21 patients to have deletions of chromosome 22q11 (DiGeorge and associated syndromes), suggesting a region on this chromosome may harbor a TOF susceptibility gene. [5] In an earlier study comparing patients who had TOF with and without chromosome 22q11 deletion, every patient with TOF and 22q11 deletion was found to have an additional conotruncal anomaly. [6]Alagille syndrome, a syndrome with cardiovascular phenotypes ranging from mild pulmonic stenosis to TOF with severe pulmonary obstruction, has been found to be due to mutations in the Jagged1 gene. [7] Additionally, mutations in Jagged1 have been associated with nonsyndromic forms of TOF. [8] A prospective study looking for mutations in NKX2.5 in patients with known TOF found approximately 4% of patients with nonsyndromic TOF to have a mutation in NKX2.5. [9]
Increasing evidence suggests environmental factors may play a significant role in some cases of CHD. [10] Maternal diabetes, maternal phenylketonuria, [11] and maternal ingestion of retinoic acids [12] or trimethadione [13] have all been associated with an increased risk of CHD.
Risk Factos
Some conditions or factors that occur during pregnancy may raise your risk of having a child who has tetralogy of Fallot. These conditions and factors include:
- German measles (rubella) and some other viral illnesses
- Poor nutrition
- Alcohol use
- Age (being older than 40)
- Diabetes
The morphologic abnormality is anterior and cephalad deviation of the muscular outlet of the ventricular septum, which causes the 4 classic findings: (1) a malalignment ventricular septal defect (VSD), (2) aorta overriding the VSD, (3) right ventricular outflow tract obstruction, (4) secondary concentric right ventricular hypertrophy.
This was classically described by Dr. Etienne-Louis Arthur Fallot, a pathologist, who described it in 1888 and coined the term "la maladie bleue" (blue-baby syndrome).
The cyanosis associated with this condition is due to right-to-left shunting of deoxygenated blood at the level of the VSD. Historically, children with TOF presented with cyanosis that was progressive and life-limiting; untreated children with TOF would typically squat down, which would lead to increased pulmonary blood flow. [1]
Classification
Variants of TOF
There is no standard classification for TOF, but many experts would use the following classification:
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Cyanotic TOF (also know as blue tet): infants with TOF and moderate to severe pulmonary obstruction are cyanotic at birth due to right-to-left shunting of deoxygenated blood from the right ventricle across the ventricular septal defect (VSD) to the body.
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Acyanotic TOF (also know as pink tet): infants with TOF and mild pulmonary obstruction are commonly acyanotic because there is little or no right-to-left shunting of blood at the ventricular level. These patients still undergo complete intracardiac repair.
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Pulmonary atresia/VSD: sometimes referred to as TOF with pulmonary atresia and is anatomically and physiologically very different. It is often associated with malformation of the central pulmonary arteries.
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Absent pulmonary valve syndrome: sometimes referred to as TOF with absent pulmonary valve. It is often associated with tracheobronchial compression and malformation.
Types of congenital heart defects vary and may be classified as cyanotic or acyanotic. If all types of defects are included, estimates of overall incidence may be as high as 9 per 1000 live births, with an overall increase if a first-degree relative has CHD. [3]
Acyanotic defects include atrial septal defects, isolated ventricular septal defects, and coarctation of the aorta.
Cyanotic defects include TOF, total anomalous pulmonary venous return, transposition of great vessels, tricuspid atresia, persistent truncus arteriosus, and hypoplastic left-heart syndrome.
TOF is the most common cyanotic congenital heart defect and is estimated to account for 4% to 9% of congenital heart defects overall, or in the range of 0.262 to 0.392/1000 live births. [2]