fact, in Noonan subjects with PTPN11 mutations, a higher prevalence of pulmonary valve stenosis has been recognized.67 On the other hand, hypertrophic cardiomyopathy is overrepresented in Noonan patients with RAF1 mutations and in LEOPARD patients with specific mutations in PTPN11.68,75 Also in patients with RIT1 mutated gene, a more severe cardiac phenotype has been described.94 Ellis-Van Creveld Syndrome Clinical Features The Ellis–van Creveld (EVC) syndrome is an autosomal recessive chondroectodermal dysplasia belonging to the group of short rib polydactyly syndromes and characterized by skeletal and craniofacial abnormalities associated with dysplastic teeth and nails (Table 77.8).95,96 The skeletal anomalies include postaxial polydactyly of hands and feet (Fig 77.7), short ribs, thoracic anomalies, short limbs, and fusion of carpal bones Craniofacial features are characterized by multiple labiogingival frenum, premature eruption of teeth or neonatal teeth, small conical teeth, and missing primary or permanent teeth Table 77.8 Prevalence of Clinical Features in Patients With Ellis–van Creveld Syndrome Clinical Feature Postaxial polydactyly of hands and feet Oral frenula Narrow thorax with short ribs Dental anomalies Short stature Congenital heart defect Atrioventricular canal defect, with/without common atrium, with/without left superior vena cava Heterotaxia Atrial septal defect, ostium secundum type Aortic coarctation Other Ectodermal defects Cleft lip Frequency (%) 100 95 80 70 60 50–60 80 5 50 30 FIG 77.7 Polydactyly in Ellis-van Creveld syndrome Cardiac Defects Approximately 60% of affected individuals have a CHD, more frequently AVCD associated with common atrium with persistent left superior vena cava and unroofed coronary sinus (see Table 77.8).96,97 The association between AVCD and common atrium is rare in the nonsyndromic patients, whereas it is relatively common in EVC syndrome96,97 and in heterotaxy syndrome.98 Leftward displacement of the atrial septum with consequent double-outlet right atrium can be present, as well as left-sided obstructive lesions In these patients, severe thoracic anomalies and left-sided obstructions can represent risk factors for cardiac surgery Delayed surgical repair of CHDs reduces postoperative morbidity and improves survival.99 Genetic Defect EVC syndrome is a ciliopathy due to mutation localized in chromosome 4p16 encompassing EVC1 and EVC2, two nonhomologous genes closely located in a head to head configuration.95 In addition, variants in WDR35100 and DYNC2LI1101 genes have been causally related to EVC syndrome Experimental studies investigating molecular pathways and developmental processes perturbed in EVC syndrome have demonstrated that EVC genes are intracellular components of the hedgehog signal transduction pathway that is required for normal transcriptional activation of the Indian hedgehog (Ihh) target genes.95 In particular, EVC is a positive mediator of the Ihh-regulated bone growth that localizes at the base of chondrocyte cilia Kabuki Syndrome Clinical Features Kabuki syndrome is a genetically heterogeneous disorder characterized by developmental delay, growth defect with feeding difficulties, skeletal anomalies, CHD, renal malformations, anorectal anomalies, persistence of fetal fingertip pads, and distinct facial anomalies (Table 77.9), including sparse eyebrows, long palpebral fissures, eversion of the lateral third of the lower eyelids, pillowed lower lip, and large everted ears (Fig 77.8).102,103 Table 77.9 Prevalence of Clinical Features in Patients With Kabuki Syndrome Clinical Feature Facial anomalies Intellectual disability Hypodontia Persistent fetal fingerpads Hypotonia/motor developmental delay Joint laxity Congenital heart defect Aortic coarctation Bicuspid aortic valve Ventricular septal defect, perimembranous subaortic Atrial septal defect, ostium secundum Conotruncal heart defects Other Feeding difficulties Short stature Cleft lip/palate Urogenital anomalies Frequency (%) 100 90 60–100 70–90 50–90 40–90 70 20 20 15 15 15 15 65–75 60 15–50 30–40