Ocular coloboma Congenital heart defect Conotruncal heart defect Atrioventricular canal Septal defects Other Growth deficiency Choanal atresia or stenosis Genital hypoplasia Cranial nerve dysfunction Cleft lip and/or palate Tracheoesophageal fistula Renal anomalies 80–90 75–85 50 25 15 10 70–80 50–60 50–60 40 15–20 15–20 10 Cardiac Defects CHDs are present in 75% to 85% of individuals with CHARGE syndrome and are often complex Many types of heart defects occur, including conotruncal anomalies (tetralogy of Fallot, interrupted aortic arch, perimembranous ventricular septal defect, double-outlet right ventricle, and truncus arteriosus), aortic arch anomalies (vascular ring, aberrant subclavian artery), AVCDs (alone or associated with tetralogy of Fallot), and septal defects (see Table 77.13).130,131 The association between AVCD and tetralogy of Fallot represents a cardiac phenotype with strong genetic characteristics, and CHARGE syndrome is the second genetic condition with this cardiac phenotype after Down syndrome.132 Genetic Defect CHD7, encoding the chromodomain helicase DNA binding protein, is the only gene known to be associated with CHARGE syndrome.133 Pathogenetic variants or intragenic rearrangements in CHD7 are detected in 65% to 70% of patients with CHARGE syndrome VACTERL Association Clinical Features VACTERL association is characterized by the presence of at least three of the following congenital malformations: vertebral defects (Fig 77.10), anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities (Table 77.14).134,135 In addition, patients may also have other congenital anomalies Significant morbidity is associated with the malformations, but neurocognitive function is usually normal FIG 77.10 Vertebral anomalies in VACTERL association Table 77.14 Prevalence of Clinical Features in Patients With VACTERL Syndrome Clinical Feature Genitourinary malformation Vertebral defect Anorectal malformation Esophageal atresia Congenital heart defect Conotruncal heart defect Septal defect Heterotaxia Frequency (%) 80–90 60–80 55–90 50–60 40–80 30 30 20 Left-sided obstruction Anomalous pulmonary venous return Other Radial defect Cognitive deficit Facial anomalies 10 5 40–50 15–20 15 Cardiac Defects Cardiac malformations have been reported in approximately 40% to 80% of patients with VACTERL association.136–138 CHDs may range from severe structural defects incompatible with life or necessitating several stages of surgery, to subtle anatomic defects Several categories are diagnosed, including conotruncal defects, heterotaxia, AVCD, and septal defects (see Table 77.14) (The study of risk factors for mortality after repair of conotruncal anomalies are showing that VACTERL syndrome is affecting adversely the surgical outcome for predominant noncardiac anomalies.) The study on risk factors affecting mortality after repair of conotruncal anomalies by Michielon et al revealed that VACTERL syndrome negatively impacted the surgical outcomes.139 Genetic Defect There is evidence for strong genetic heterogeneity of VACTERL association Although familial clustering has been reported, it is in fact rare The majority of cases are reported as isolated individuals in the families The Sonic Hedgehog pathway genes have been suspected to be implicated in the etiology of the disease because animals with mutations have features of VACTERL association.140 In addition, mutations or deletions in FOXF1, a gene linked to the Sonic Hedgehog, result in a VACTERL-like phenotype.141 Furthermore, disruption of pathways involving Hox and retinoic acid signaling have been suspected to be involved.142,143 Among environmental influences, maternal diabetes can be cited.134,135 Goldenhar Syndrome Clinical Features The Goldenhar syndrome (or oculo-auriculo-vertebral spectrum) is characterized by unilateral microtia, hemifacial microsomia with mandibular hypoplasia,