FIG 77.4 Facial appearance of deletion 22q11.2 syndrome Table 77.5 Prevalence of Clinical Features in Patients With Deletion 22q11.2 Syndrome Clinical Feature Facial anomalies Learning difficulties Congenital heart defect Pulmonary atresia with ventricular septal defect Tetralogy of Fallot Ventricular septal defect, subaortic Interrupted aortic arch Truncus arteriosus Vascular ring Atrial septal defect Other Immune deficiency Palatal anomalies Neonatal hypocalcemia Renal anomalies Skeletal anomalies Ocular anomalies Anal anomalies Frequency (%) 100 70–90 75 25 25 15 10 10 75 70 50 30 15 Cardiac Defects CHDs are present in 75% of patients with deletion 22q11.2; commonly, conotruncal defects are the major cause of mortality (>90% of all deaths) Anatomic types include tetralogy of Fallot, pulmonary atresia with ventricular septal defect, interrupted aortic arch, mainly type B, truncus arteriosus, and ventricular septal defect (see Table 77.5).44–46 Commonly seen aortic arch anomalies, either in isolation or in association with intracardiac anomalies, are cervical aortic arch, double aortic arch, right-sided aortic arch, and abnormal origin of the subclavian arteries.47 A subset of affected individuals are found to have dilated aortic root.48 The syndrome is sometimes associated with peculiar aspects of cardiac anatomy In fact, discontinuity, diffuse hypoplasia, crossing of the pulmonary arteries, and major aortopulmonary collateral arteries may be recognizable patterns for tetralogy of Fallot (also in the setting of an absent pulmonary valve) and for pulmonary atresia with ventricular septal defect Discontinuity of the pulmonary arteries may be characteristic for truncus arteriosus type A3 (according to Van Praagh classification), whereas hypoplasia of infundibular septum is present in both tetralogy of Fallot and interrupted aortic arch.46,49–51 The analysis of surgical results show that these additional cardiac defects do not worsen surgical prognosis, and deletion 22q11.2 does not represent a surgical risk factor when syndrome-specific perioperative management is adopted Longterm survival of patients with conotruncal cardiac defects and deletion 22q11.2 is similar to that of patients with nonsyndromic conotruncal defect Patients with pulmonary atresia and major aortopulmonary collateral arteries are an exception in terms of mortality risk, probably due to the complexity of the pulmonary artery anatomy.52–54 Major systemic to pulmonary collaterals may be responsible for bronchomalacia and persistent airway hyperresponsiveness with bronchospasm in the preoperative and postoperative periods In patients with deletion 22q11.2, the perioperative care should be focused on prevention of hypocalcemia and infections, including analysis of lymphocyte populations prior to transfusion, administration of irradiated blood products, and aggressive treatment of perioperative infections, and perhaps antifungal prophylaxis in selected situations.39 Genetic Defect The syndrome is caused by microdeletions in the 22q11.2 chromosomal region Most patients have a 3-Mb deletion, resulting from nonallelic homologous recombination between the two largest low-copy repeats flanking the DiGeorge critical region.41,55 More than 40 genes map within the DiGeorge critical region TBX1 gene is known to be a crucial gene in the syndrome and likely responsible for many heart and vascular anomalies.56 Considering the highly variable phenotypic expression of the syndrome, it is possible that deletion 22q11.2 alone cannot explain all the manifestations of the disease, and the sensitivity of individual genes within the 22q11.2 region to gene dosage variants and additional “modifying” variants outside the 22q11.2 region also account for the manifestations.11,57 Williams Syndrome Clinical Features Williams syndrome is characterized by typical facial anomalies, CHD, connective tissue abnormalities, motor developmental delay and hypotonia, intellectual disability, feeding difficulties in infancy, growth abnormalities, and endocrine anomalies (hypercalcemia, hypothyroidism, and early puberty) (Table 77.6).58,59 Facial anomalies include bitemporal narrowing, periorbital fullness, a stellate iris pattern, strabismus, malar flattening, short nose with anteverted nares, long philtrum, wide mouth with thick lips, and large ear lobes (Fig 77.5) Table 77.6 Prevalence of Clinical Features in Patients With Williams Syndrome Clinical Feature Facial anomalies Developmental delay Short stature Congenital heart defect Supravalvar aortic stenosis Peripheral pulmonary artery stenosis Septal defect Coarse voice Low birth weight Microcephaly Strabismus Frequency (%) 100 90 85 80 70 20 10 80 80 70 45