Table 77.2 Prevalence of Clinical Features in Patients With Down Syndrome Clinical Feature Developmental delay Facial anomalies Congenital heart defect Atrioventricular canal defect Ventricular septal defect, inlet type Atrial septal defect Tetralogy of Fallot Other Duodenal atresia Hirschsprung disease Anal atresia or stenosis Ocular anomalies Frequency (%) 100 100 50 40 25 20 10 20 10 Cardiac Defects CHDs are diagnosed in approximately 50% of patients but the incidence is lower in those with trisomy 21 mosaicism.13 The classic studies reported that the more frequent cardiac defect is AVCD, followed by atrial septal defects, ventricular septal defects, and tetralogy of Fallot (see Table 77.2).14 However, in Asian and Native American children with Down syndrome the prevalence of various types of cardiac defect is quite different in comparison with the white population The most common cardiac defect in Asian and Native American children with Down syndrome is similar from a genetic point of view15 and is the ventricular septal defect followed by the AVCD that is prevalent in whites.14 This finding suggested that, in persons with Down syndrome, other genetic factors (different from trisomy 21) may be involved in the pathogenesis of the various types of CHD Some anatomic patterns of CHD are quite distinct in the condition In particular, the complete form of AVCD, which is prevalent in Down syndrome, is rarely associated with other cardiac anomalies, excluding tetralogy of Fallot Particularly, left-sided obstructive lesions, including right ventricular dominance, subaortic stenosis, and aortic coarctation, are rare, in contrast to the AVCD patients with normal karyotype Anomalies of the visceral situs, ventricular loop, and transposition of the great arteries are virtually absent in these patients.16 The inlet type ventricular septal defect (VSD) is prevalent in patients with Down syndrome, whereas muscular and subarterial septal defects are very rare.17 A major impact in cardiologic medical and surgical management of patients with Down syndrome is due to the observed favorable anatomic characteristics of the heart In fact, surgical results of both the partial and the complete type AVCD are better in patients with Down syndrome compared with nonsyndromic children, with the exception for the known tendency to develop pulmonary hypertension in Down syndrome.18 Down syndrome has been identified as the most significant risk factor for atrioventricular block after surgical closure of perimembranous VSD, and this should be explained considering the prevalence of inlet extension of the malformation Particular attention in the perioperative period in Down syndrome patients should be addressed to the associated noncardiac issues, such as respiratory obstructive disease, immune system disorders, and infections Genetic Defect Down syndrome is caused by trisomy of chromosome 21 The overexpression of genes mapping on this chromosome should be considered related to the etiology of malformations and developmental delay in Down syndrome, although the molecular basis regulating the presence and anatomy of CHD is still unclear A critical region for CHD has been identified on chromosome 21, but variants in genes mapping on different chromosomes have also been considered to be etiologically involved, such as CRELD1, FBLN2, FRZB, and GATA5.19 In addition, a potential role of copy number variations mapping on chromosomes different from the 21 has been evidenced in the pathogenesis of CHD in Down syndrome.20 These genetic variants may explain the variability of cardiac phenotype and the ethnic differences Some recent observations in mouse models have pointed to a role of the Shh signaling pathway in Down syndrome Cerebral, skin, liver, and intestine mice trisomic cells have shown defective mitogenic Shh activity with cell proliferation impairment due to a higher expression of Ptch1, a receptor normally repressing the Shh pathway.21 In addition, subcutaneous administration of the Shh pathway agonist SAG to trisomic Ts65Dn mice at birth resulted in an increased proliferation of granule cell precursors in the cerebellum.22 Turner Syndrome Clinical Features Clinical characteristics include short stature, gonadal dysgenesis, CHD, renal malformation, pectus excavatum, cubitus valgum, pterygium colli, lymphedema, and facial anomalies, including palpebral ptosis with elongated fissures, epicanthal folds, flat nasal bridge, and downturned mouth (Table 77.3 and Fig 77.2).23 Most patients with Turner syndrome have intelligence falling within the normal range The phenotype is highly variable between affected subjects Table 77.3 Prevalence of Clinical Features in Patients With Turner Syndrome Clinical Feature Short stature Gonadal dysgenesis Pterygium colli/Short neck Facial anomalies Lymphatic anomalies Skeletal anomalies Hypertension Renal anomalies Congenital heart defect (45,X karyotype) Aortic coarctation alone Bicuspid aortic valve alone Aortic coarctation and other cardiovascular anomalies Aortic valve stenosis Hypoplastic left heart syndrome Anomalous pulmonary venous return Other Conductive or sensorineural deafness Developmental delay Frequency (%) 95 95 80 75 60 50 45 25–45 25–40 25 25 10 10 5 20 25