Tetralogy of Fallot
Tetralogy of Fallot (ToF) is one of the most common cyanotic heart defects with an incidence of 3-5 per 10,000 live births, accounting for approximately 7-10 % of congenital heart defects in liveborn children81. Historically, the underlying anatomic condition was attributed to Etienne-Louis Fallot in 1888, who introduced the term ‘La Maladie Bleue’, the Blue Disease82,83. However, it was the merit of the Danish anatomist Niels Stenson, who described this pathology during a necropsy of a malformed fetus with ectopia cordis already in 167184. In 1924, Maude Abbott coined the term ‘Tetralogy of Fallot’, as Fallot was the first to link the defining classical clinical features: RV outflow tract obstruction (RVOTO), ventricular septal defect, overriding aorta, and right ventricular hypertrophy.
Embryologically, anterocephalad deviation of the developing outlet ventricular septum together with hypertrophy of septoparietal trabeculations determine both the RV outflow tract obstruction and the malaligned ventricular septal defect with an overriding aorta81. The exact cause of this combination of lesions remains unknown, and its etiology is thought to be multifactorial including both environmental and genetic factors. The reported incidence of chromosomal anomalies in ToF is 29 % (including microdeletion of 22q11.2). According to a recent systematic review, 22q11.2 microdeletion is apparently three times more common in ToF with PA. Notably, aneuploidies are more often in classical ToF85. Other concomitant cardiac anomalies comprise an atrioventricular septal defect (AVSD), a right-sided aortic arch (RAA), an anomalous origin of the coronary arteries, a left persistent superior vena cava and total anomalous pulmonary venous return (TAPVR). In subset of cases, ToF is complicated by a severely underdeveloped or even absent pulmonary valve that is replaced by a thickened infundibulum and rudimentary valve tissue at the level of the pulmonary valve annulus, with usually massively dilatated pulmonary arteries, as stated below.
In clinical practice, there is a broad spectrum of this condition. The most common variety of ToF consists of a mild-to-moderate RVOTO and normally sized branch pulmonary arteries. In utero , RV hypertrophy is almost always absent as the pressure gradient between of right and left ventricles is rather low, and the four-chamber cardiac view appears to be normal. On the other hand, there may also be complete obstruction of the RVOT, which is similar to pulmonary atresia with VSD. The pulmonary blood flow in this case is maintained from the aorta either retrogradely via the ductus arteriosus supplying the PAs or via major aortopulmonary collateral arteries (MAPCAs). In figure 7, the cardiac anatomic changes in a fetus with ToF/PS are illustrated. Notably, the 3VT and 4CV views are normal including the cardiac axis, and the DA is patent, as in 80-90 % of all ToF cases. A perimembraneous VSD is clearly seen in the 5CV and LVOT views with an overriding aorta. The main pulmonary artery is slightly smaller (than the ascending aorta) in the RVOT and ductal arch views. Additional color Doppler interrogation revealed laminar, nonturbulent flow across the PV, precluding a hemodynamically significant RVOTO. Yeo and Romero published a report of a case of ToF/PA analyzed with the FINE method and clearly demonstrated a narrow and atretic RVOT86. It has previously been shown that an abnormal cardiac axis in fetuses with ToF is highly predictive of the presence of pulmonary atresia and a right-sided aortic arch and is linked to postnatal death87. In this regard, a recent study on the prevalence of genetic abnormalities supported the impact of cardiac angle assessment as levorotation of the cardiac axis was noticed in two-third of ToF cases with genetic anomalies (assessed by chromosomal microarray analysis)88. Lv et al. published on a big data analysis for the differential diagnoses of ToF; based on their results, the PA/Ao ratio constitutes the primary parameter to distinguish ToF from large malalignment VSD, which is in line with observations by Wu and colleagues, who calculated 11 different cardiovascular dimensions applied on STIC volumes and were able to show that all fetuses with ToF had abnormal Ao z-scores and reduced PA/Ao ratios89,90. A recent multicenter study confirmed these parameters to be the most valid predictors of neonatal intervention (PV:AoV ratio <0.6, PV:AoV z-score difference ≥5)91.