Many other lesions can coexist with tetralogy Patency of the oval foramen is common, and a deficiency of the floor of the oval fossa is far from infrequent In addition to a second inlet muscular ventricular septal defect, straddling of the tricuspid valve or the presence of a common atrioventricular valve, features already emphasized, the most important associated lesion from the stance of the surgeon is probably anomalous origin of the anterior interventricular coronary artery from the right coronary artery A right aortic arch, though not of functional importance, is also common When detected, it alerts to the diagnosis of tetralogy Aortic dilation and valvar incompetence is more common in older patients Morphogenesis The notion that TOF reflects malseptation of the arterial segment of the developing heart has a long pedigree and is supported by observations concerning naturally occurring infundibular lesions in Keeshond dogs.5 These animals show a spectrum of malformations, ranging from absence of the medial papillary muscle, through presence of an interventricular communication, to a constellation of anomalies similar to tetralogy Study of embryos in which developmental stages of these malformations were observed, showed that the factory for production of the lesions was within the ventricular outflow tracts Specifically, abnormalities were found in the formation and position of the endocardial cushions, which normally fuse to septate the ventricular outlets These observations were confirmed in rats dosed with bis-diamine, with further evidence demonstrating muscularization of the proximal outflow cushions to form the subpulmonary infundibulum of the normal heart provided by observations in the developing human heart (Fig 35.11).6 FIG 35.11 Sections from human embryos showing the change in appearance of the proximal outflow cushions, which muscularize (left) to form the normal supraventricular crest (right) Both sections are taken to replicate the oblique subcostal echocardiographic projection The yellow arrow shows the embryonic interventricular communication, which is closed as the aorta is transferred to the left ventricle The findings in patients with deletion of chromosome 22q11 also support the existence of malseptation of the outflow tracts in humans and point to this being due to problems in the migration of cells from the neural crest Based on the anatomic findings, therefore, it can be said with some degree of certainty that there is malseptation of the ventricular outlets and the arterial pole of the heart at the expense of the pulmonary trunk, together with failure of normal incorporation of the aortic outflow tract into the morphologically left ventricle.2 As discussed, the abnormal attachment of the muscular outlet septum is sufficient to account for the presence of the interventricular communication and the biventricular connection of the aorta, but production of subpulmonary muscular stenosis requires additional hypertrophy of the septoparietal trabeculations The right ventricular hypertrophy is simply a hemodynamic consequence of the anatomic lesions Clinical Diagnosis The clinical presentation is dominated by the degree of muscular obstruction of the right ventricular outflow tract.11 This is sometimes modified by associated anomalies, such as persistent patency of the arterial duct, or presence of large systemic-to-pulmonary collateral arteries Presentation When Subpulmonary Obstruction Is Severe From Birth When the obstruction of the right ventricular outflow tract is severe at birth, presentation is in the neonatal period Persistent cyanosis becomes apparent within the first few hours or days of life With severe arterial desaturation, a metabolic acidosis develops that is compensated by an increased respiratory rate The concomitant fall in arterial content of carbon dioxide gives rise to a compensatory respiratory alkalosis Intercostal or subcostal recession, however, is unusual Cyanosis, which dominates the clinical picture, increases with crying, feeding, or other activities At least initially the baby does not appear unduly distressed Sometimes the pulmonary circulation is duct dependent In this setting, the degree of subpulmonary obstruction is so great that there is inadequate antegrade flow, and virtually all pulmonary blood flow is derived from a left-to-right shunt via the arterial duct Under such circumstances, spontaneous closure of the duct results in death Maintenance of ductal patency, usually by the infusion of prostaglandin E, is crucial (see later) Presentation When Subpulmonary Obstruction Is Moderate at Birth The majority of children with TOF are acyanotic at birth Consequently they often present because a systolic murmur is detected during routine examination The development of cyanosis is dependent on increasing infundibular stenosis and not on the degree of aortic override.12 This is usually noted within the first few weeks of life, but development of cyanosis may rarely be delayed to late childhood The systolic murmur, present in all patients other than those with very severe stenosis or acquired atresia, originates at the site of subpulmonary obstruction and not because of flow across the ventricular septal defect.13 At this stage, infants or children are usually asymptomatic Later, hypercyanotic spells or squatting on exercise may all occur (see further on) With improved medical surveillance, all of these symptoms are now less often encountered than even a decade ago Presentation When Subpulmonary Obstruction Is Minimal at Birth Some infants with tetralogy may uncommonly present at the age of 4 to 6 weeks with features indistinguishable from those of a large ventricular septal defect (see Chapter 28) These babies are breathless, feed poorly, gain weight poorly,