What is the embryological development of Tetralogy of Fallot?

Embryological Development of Tetralogy of Fallot

Tetralogy of Fallot (TOF) results from anterosuperior deviation of the conal or outlet septum during cardiac development, leading to the four classic components: ventricular septal defect, pulmonary stenosis, overriding aorta, and right ventricular hypertrophy. 1

Embryological Basis

Developmental Origin

• TOF develops during weeks 4-8 of embryonic development when the heart is undergoing septation and outflow tract formation
• The primary embryological defect is anterior and cephalad deviation of the infundibular septum
• This single developmental anomaly leads to all four classic components of TOF:
  1. Ventricular Septal Defect (VSD): The malalignment of the conal septum creates a subaortic VSD
  2. Pulmonary Stenosis: The deviated septum narrows the right ventricular outflow tract
  3. Overriding Aorta: The aortic valve shifts rightward, overriding the ventricular septum by less than 50% of its diameter
  4. Right Ventricular Hypertrophy: Secondary change due to outflow obstruction

Molecular and Genetic Factors

• TOF has associations with chromosomal abnormalities, particularly microdeletions of chromosome 22q11 (DiGeorge syndrome) 2
• Other genetic associations include trisomies 21,18, and 13 2
• Environmental factors such as untreated maternal diabetes, phenylketonuria, and retinoic acid exposure may contribute 2

Anatomical Spectrum

Classic TOF

• The classic form includes the four components described by the American Heart Association and American College of Cardiology 1
• The VSD is typically large and subaortic in position 3
• The pulmonary valve is often small and stenotic 3

Anatomical Variants

1. Pulmonary Atresia with VSD: The most extreme form with complete atresia of the pulmonary valve 1
2. TOF with Absent Pulmonary Valve: Characterized by absent or rudimentary pulmonary valve leaflets with aneurysmal dilation of the pulmonary arteries 4
3. TOF with Pulmonary Artery Anomalies: Including hypoplasia, stenosis, or absence (most commonly left pulmonary artery) 3
4. Pentalogy of Fallot: TOF with an additional atrial septal defect 1

Associated Anomalies

• Secundum atrial septal defect
• Atrioventricular septal defect (especially in patients with Down syndrome)
• Right aortic arch (in approximately 25% of cases) 3
• Coronary artery anomalies (most commonly anomalous left anterior descending coronary artery) 3
• Major aortopulmonary collateral arteries (MAPCAs), especially in severe forms 5

Pathophysiological Consequences

• The degree of right ventricular outflow tract obstruction primarily determines the clinical presentation and severity 6
• With mild pulmonary stenosis, patients may present as "pink tetralogy" with minimal cyanosis 3
• Severe pulmonary stenosis or atresia results in right-to-left shunting across the VSD, causing cyanosis
• The additional ASD in Pentalogy of Fallot increases right-to-left shunting and can exacerbate cyanosis 1

Clinical Implications of Embryological Development

• Understanding the embryological basis helps explain the anatomical spectrum and associated anomalies
• The degree of conal septum deviation correlates with severity of pulmonary stenosis
• Coronary artery anomalies, which develop during the same embryological period, must be identified before surgical repair 3
• The embryological development influences surgical approach and timing of intervention 1

Diagnostic Considerations

• Echocardiography remains the primary diagnostic tool, but CT and MRI provide additional anatomical details 4
• Prenatal diagnosis is increasingly common due to improved fetal echocardiography 7
• Defining the course of coronary arteries is essential before surgical repair 3

TOF represents a spectrum of anatomical abnormalities stemming from a single embryological defect with varying clinical manifestations based on the severity of right ventricular outflow tract obstruction.