FIG 77.8 Facial appearance of Kabuki syndrome Cardiac Defects The prevalence of CHD in Kabuki syndrome is approximately 70% Anatomic types include aortic coarctation and other left-sided obstructive lesions (bicuspid aortic valve, hypoplastic left heart), septal defects, and conotruncal anomalies (see Table 77.9).104–106 Patients with aortic malformation can have additional anomalies of the mitral valve, consisting in mitral stenosis with supramitral ring, dysplastic mitral valve, and bicuspid aortic valve These multiple left-sided obstructions are similar to those observed in the spectrum of the so-called Shone complex,107 identified as the association of aortic coarctation, membranous subaortic stenosis, bicuspid aortic valve, mitral stenosis with “parachute” mitral valve with single papillary muscle, and supramitral ring Aortic dilatation has also been seen in association with congenital aortic lesions in patients with Kabuki syndrome, so these patients are at increased risk of aortic aneurysm.106 For this reason, annual monitoring for aortic dilatation is suggested In addition, a predisposition to vascular hypertension should also be considered in patients with Kabuki syndrome Septal defects are also frequent in Kabuki syndrome and include atrial septal defect of ostium secundum type and perimembranous subaortic ventricular septal defect, and conotruncal defects also occur in a minority of the patients Genetic Defect Kabuki syndrome is genetically heterogeneous because five causative genes are known at present The first identified and more frequently involved gene is KMT2D (MLL2), mapping to 12q13.12,108 and is implicated in 60% to 80% of the cases The KDM6A gene, mapping to Xp11.3, is the second gene associated with Kabuki syndrome.109 More recently, three additional genes involved in a minority of patients have been identified.110–112 Alagille Syndrome Clinical Features Alagille syndrome (ALGS) is an autosomal dominant disorder involving the liver, heart, eyes, face, and skeleton The major clinical features are cholestasis, characterized by bile duct paucity on liver biopsy, posterior embryotoxon in the eye, mild facial features, and butterfly vertebrae Jaundice presents as conjugated hyperbilirubinemia in the neonatal period (Table 77.10).113 In approximately 15% of affected individuals, the liver disease progresses to cirrhosis and liver failure, necessitating liver transplantation Cognitive development is usually normal Table 77.10 Prevalence of Clinical Features in Patients With Alagille Syndrome Clinical Feature Chronic cholestasis Congenital heart defect Peripheral pulmonary stenosis Tetralogy of Fallot Septal defects Aortic coarctation Other Bile duct paucity Facial anomalies Frequency (%) 95 95 65 15 5 10 75–85 70–90 Eye embryotoxon Vertebral anomalies Renal anomalies Developmental delay/intellectual disability 60–80 40–50 25–40 15 Cardiac Defects Cardiac defects occur in 90% of the patients The pulmonary vasculature (pulmonary valve, pulmonary artery, and its branches) is most commonly involved Pulmonic stenosis (peripheral and branch) is the most common cardiac finding, but tetralogy of Fallot (with and without pulmonary atresia), ventricular septal defect, atrial septal defect, aortic stenosis, and coarctation of the aorta also has been reported (see Table 77.10).113,114 In children with tetralogy of Fallot (with and without pulmonary atresia) and ALGS, the multiple and severe peripheral pulmonary artery stenosis may represent an important risk factor at corrective operation Genetic Defect Two genes are known to cause ALGS: JAG1 and NOTCH2.115–117 Mutations in JAG1 are detected in 90% of the patients, whereas pathogenic variants in NOTCH2 are diagnosed in 1% to 2% of patients with ALGS The phenotype of ALGS caused by mutation of JAG1 is indistinguishable from the phenotype caused by mutation of NOTCH2 Holt-Oram Syndrome Clinical Features Holt-Oram syndrome is an autosomal dominant disease characterized by upper extremity malformations involving radial, thenar, or carpal bones, CHD, or cardiac conduction disease (Table 77.11).118 Upper limb malformations can range from triphalangeal or absent thumb to phocomelia (Fig 77.9) Intermediate presentations may also be observed Sloping shoulders and restriction of shoulder joint movement can also be present Table 77.11 Prevalence of Clinical Features in Patients With Holt-Oram Syndrome