Clinical Feature Thumb anomaly Congenital heart defect Atrial septal defect, ostium secundum Ventricular septal defect, muscular Tetralogy of Fallot Atrioventricular canal defect Anomalous pulmonary venous return Other Shoulder anomalies Shortening of the upper arm Radial hypoplasia Cardiac conduction disease Frequency (%) 85 75 40 30 10 5 10 75 45 40 40 FIG 77.9 Radial hypoplasia in Holt-Oram syndrome Cardiac Defects A congenital heart malformation is present in 75% of individuals with HoltOram syndrome Anatomic types include atrial septal defect ostium secundum type and ventricular septal defect, particularly involving muscular septum (see Table 77.11).119,120 More complex CHDs, such as tetralogy of Fallot, have also been described, Patients with Holt-Oram syndrome with or without CHD are at risk for cardiac conduction disease, including sinus bradycardia and first-degree atrioventricular block Genetic Defect The majority of the patients have heterozygous TBX5 pathogenic variants, a gene member of the homeobox gene family acting as transcription factor.121 Adams-Oliver Syndrome Clinical Features Adams-Oliver syndrome is a rare genetic disorder characterized by aplasia cutis congenita and terminal transverse limb defects (Table 77.12).122 Cardiac defects can be associated, such as structural or functional vascular abnormalities.123 In addition, anomalies in internal organs, including the central nervous, pulmonary, gastrointestinal, and genitourinary systems have also been described (see Table 77.12) Table 77.12 Prevalence of Clinical Features in Patients With Adams-Oliver Syndrome Clinical Feature Transverse terminal limb defects Cutis aplasia Congenital heart defect Left-sided obstructive lesions Septal defects Other Neurologic anomalies Cardiac Defects Frequency (%) 85 80 25 50 30 20 20 CHDs are occurring in 13% to 20% of the patients, and different anatomic types have been reported, including left-sided obstructive lesions, septal and conotruncal defects, and tricuspid atresia (see Table 77.12).123–125 Left-sided obstructive lesions, particularly anomalies at multiple levels characteristic of Shone complex (parachute mitral valve, hypoplastic left ventricle, bicuspid aortic valve, and hypoplastic aortic arch),126 and vascular abnormalities, of which cutis marmorata telangiectatica congenita are the most frequently described lesions Other vascular defects include lower limb vasculature abnormalities, portal and cortical renal vein defects, and disorders of the pulmonary vasculature, including bronchopulmonary hemangioma, pulmonary arteriovenous malformations, and pulmonary hypertension.123–125 Genetic Defect Adams-Oliver syndrome is primarily inherited as an autosomal dominant trait with variable phenotypic expression; autosomal recessive transmission has also been identified in several families The syndrome is a heterogeneous disorder with mutations in different genes.126–128 CHARGE Syndrome Clinical Features CHARGE is an acronym for ocular coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies (Table 77.13).129 Cranial nerve dysfunction resulting in hyposmia or anosmia, and unilateral or bilateral facial palsy is often present Ear anomalies manifest as abnormal outer ears, ossicular malformations, Mondini defect of the cochlea, and absent or hypoplastic semicircular canals Growth deficiency, orofacial clefts, and tracheoesophageal fistula can also be present Table 77.13 Prevalence of Clinical Features in Patients With CHARGE Syndrome Clinical Feature Characteristic ear dysmorphism Middle ear malformation Developmental delay Frequency (%) 80–100 80–100 70–100