Tetralogy of Fallot

Risk factors

• 22q11.2 microdeletion (DiGeorge / velocardiofacial syndrome)
• Trisomy 21, trisomy 13/18, Alagille syndrome, CHARGE association
• Maternal diabetes, phenylketonuria, retinoic acid exposure
• Family history of CHD

Pathophysiology

RVOT obstruction creates resistance to pulmonary blood flow. Pressure equalization through the VSD allows desaturated RV blood to enter the overriding aorta, producing systemic cyanosis. The degree of cyanosis is inversely related to pulmonary blood flow — a fall in systemic vascular resistance (crying, exertion, fever) or an increase in dynamic infundibular obstruction (catecholamine surge, hypovolemia) promotes right-to-left shunting across the VSD and worsening cyanosis (the mechanism of hypercyanotic 'tet spells', not ductal closure); raising SVR (squatting, knee-chest position, phenylephrine) reduces the shunt and is the basis of spell treatment. 'Pink TOF' has minimal RVOT obstruction with predominantly left-to-right shunting.

Clinical presentation

Differential diagnosis

• Transposition of the great arteries (D-TGA) — Severe cyanosis at birth, ductal-dependent; CXR may show 'egg on a string'; echo confirms
• Tricuspid atresia — Cyanosis with left axis deviation on ECG (unusual in a cyanotic infant); echo shows atretic tricuspid valve
• Truncus arteriosus — Single great artery, often with HF rather than cyanosis as primary feature
• Total anomalous pulmonary venous return — Severe cyanosis and pulmonary edema; 'snowman' on CXR in supracardiac type
• Critical pulmonary stenosis — Cyanosis, often ductal-dependent; loud ejection murmur; no VSD or overriding aorta
• Pulmonary atresia with VSD (extreme TOF) — Continuum with TOF; ductal-dependent pulmonary flow
• Eisenmenger syndrome — Late-onset cyanosis in setting of prior L-to-R shunt; different natural history

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Newborn / infant<br/>cyanosis or murmur] --> B[Echo: four-feature TOF]
  B --> C{Severe<br/>RVOT obstruction or<br/>pulmonary atresia?}
  C -->|Yes| D[PGE1 to maintain PDA<br/>± BT shunt]
  C -->|No| E[Stable — outpatient<br/>follow-up to surgery]
  E --> F[Elective complete repair<br/>at 3-6 months]
  D --> F
  G[Hypercyanotic 'tet spell'] --> H[Knee-to-chest<br/>O2, IV fluid<br/>morphine]
  H --> I[Phenylephrine<br/>esmolol<br/>± bicarbonate]
  F --> J[Lifelong follow-up:<br/>PR, RV size,<br/>arrhythmia risk]
  J --> K[Pulmonary valve<br/>replacement when<br/>RV criteria met]

Treatment

Complications

• Hypercyanotic 'tet' spells with risk of stroke, seizure, or death
• Cerebrovascular events: ischemic stroke from paradoxical embolism, cerebral abscess (especially in unrepaired cyanotic disease)
• Polycythemia, hyperviscosity, iron deficiency (with paradoxically high hematocrit)
• Post-repair: chronic pulmonary regurgitation, RV dilation, RV dysfunction, ventricular arrhythmias, sudden cardiac death
• Branch pulmonary artery stenosis, recurrent RVOT obstruction, residual VSD
• Aortic root dilation and aortic regurgitation in adulthood

PANCE pearls

• Squatting (or knee-to-chest position) increases systemic vascular resistance and reduces the right-to-left shunt — a self-administered remedy in children with TOF.
• 'Tet spell' triad: agitated/crying child + sudden worsening cyanosis + DECREASE in murmur intensity (because pulmonary flow drops).
• Boot-shaped heart on CXR comes from uplifted apex (RVH) and concave pulmonary trunk; right aortic arch is present in ~25%.
• 22q11.2 deletion: screen with FISH or chromosomal microarray; associated with hypocalcemia, immunodeficiency, palatal abnormalities, and learning differences.
• Long-term complication after repair is chronic pulmonary regurgitation → RV dilation/dysfunction → ventricular arrhythmias; serial cardiac MRI guides timing of pulmonary valve replacement.

References

• AHA/ACC 2018 — 2018 AHA/ACC Guideline for the Management of Adults with Congenital Heart Disease (Stout et al., Circulation 2019)
• AHA Scientific Statement 2024 — Long-Term Management of Right Ventricular Outflow Tract Dysfunction in Repaired Tetralogy of Fallot: A Scientific Statement From the American Heart Association (Geva et al., Circulation 2024;150:e689-e707)
• INDICATOR cohort — A propensity score-adjusted analysis of clinical outcomes after pulmonary valve replacement in tetralogy of Fallot (Bokma et al., Heart 2018;104:738-744)