**2.3. William's syndrome**

The phenotype of Williams' syndrome is variable, but includes characteristic facies (flared eyebrows, bright stellate irides and wide mouth), specific personality and cognitive features, and infantile hypercalcaemia in addition to cardiac anomalies. The prevalence is 1 in 10,000–20,000. Children with Williams's syndrome can be diagnosed at different ages and present with a broad range of clinical features [35]. Early in life, feeding disorders and growth retardation are common. Hypercalcemia is seen in 15% of infants and usually resolves over time [36]. Cardiac anomalies are present in 55–80% of individuals with William's syndrome, which typically include supravalvar aortic stenosis and/or supravalvar pulmonary stenosis [37, 38]. The degree of the cardiovascular involvement and the relative involvement of the pulmonic or aortic vessels varies widely. By 1 year of age 41% of the pulmonary lesions will have improved, whereas 73% of the aortic lesions will have progressed [38].

colobomata (79%), heart defects (85%), choanal atresia (57%), growth and developmental retardation (100%), Genital hypoplasia (34%) and Ear anomalies (91%). Additional problems include renal anomalies, facial clefts and esophageal atresia [54]. CHD has been always been

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The frequency of the CHD range from 74–92% in CHD7 mutation-positive cases [55, 56], as compared to 71% in CHD7 mutation- negative individuals in one report [55]. A wide range of CHD has been reported in CHARGE syndrome, including conotruncal and aortic arch anomalies consistently over represented in clinical series [56]. The frequency of the CHARGE syndrome has been reported to range from 1 per 10,000 to 1 per 15,000 live births, although one population-based study estimated a frequency of 1 in 8500 live births [57]. Most of the cases of CHARGE syndrome are sporadic in occurrence, but autosomal dominant inheritance

The phenotype is described by its acronym: Vertebral defects, Anorectal anomalies, Cardiac anomalies, Tracheoesophageal fistula with Esophageal atresia, and Renal and upper Limb anomalies. A general diagnostic guideline requires three or more defects to establish the diagnosis [58]. It is usually a sporadic occurrence of unknown cause. In rare cases an association can occur in trisomy 18 [59], or trisomy 21 [60]. A cardiac anomaly is present in at least 73% of affected individuals and includes atrial septal defect (ASD), VSD, double-outlet right ven-

No definitive prenatal testing is available, but the diagnosis should be considered if antenatal ultrasound demonstrates a vertebral anomaly, absence of the fetal stomach and a cardiac anomaly with or without polyhydramnios. The management involves a multidisciplinary approach [61]. VACTERL has a low recurrence risk of 2–3%, although there are rare reports of

Alagille syndrome was originally defined as the presence of bile duct paucity on liver biopsy in conjunction with three of the following five findings: cholestasis, congenital heart disease, skeletal or ocular abnormalities or typical facial features which give the face an inverted triangle appearance (broad forehead, deep set eyes, rounded tip and pear like shape of the nose and pointed chin) [63, 64]. Alagille syndrome is an autosomal dominant condition with high penetrance (94%) and variable expressivity, which is the result of mutations or deletions in the JAG-1 gene (locus 20p11.2). De novo mutations occur in 50–60% of cases [65, 66]. Alagille syndrome is now recognized to be a genetically heterogeneous disorder. Approximately 5% of the patients with a chromosomal deletion involving one copy of the entire JAG1 gene,

The prevalence is 1 in 70,000 to 100,000 live births [68]. Cardiovascular anomalies are present 90% of the cases [68]. The most common cardiac lesion is pulmonary artery branch stenosis (PABS), tetralogy of Fallot (in up to 10% of cases), pulmonary stenosis and coarctation of the aorta [69]. If the mutation or deletion is identified in a parent, prenatal diagnosis is available

familial cases, including one of a mother and son, both with typical features [62].

whereas most will have various intragenic JAG1 mutations [67].

and germline mosaicism, have now been confirmed by molecular testing [55].

part of the core phenotype.

**2.6. VACTERL association**

tricle, TOF and dextrocardia [58].

**2.7. Alagille syndrome**

Approximately 90% of patients with the clinical diagnosis of Williams's syndrome have a deletion at chromosome 7q11.23, which can be detected by fluorescence in situ hybridization (FISH), multiplex ligation- dependent probe amplification (MLPA) and microarray technologies. The gene mapping to this region has been defined and includes the gene ELN, whose product is elastin. The deletion of this gene results in the connective tissue abnormalities associated with the CHD of Williams' individuals [39, 40]. Prenatal genetic testing can be performed on Chorionic villus sampling or amniotic fluid samples in the few pregnancies considered to be at increased risk. Neonatal diagnosis is challenging, and full features become more apparent with time. William's syndrome is transmitted in an autosomal dominant manner. Most cases are de novo occurrence and recurrence risks are 50% if a parent is affected but otherwise low (<5%) [41, 42].
