**2.6. VACTERL association**

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

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].

have improved, whereas 73% of the aortic lesions will have progressed [38].

**2.4. 22q11 deletion syndrome (DiGeorge syndrome, velocardiofacial syndrome,** 

Molecular studies demonstrate that the vast majority of patients with clinical diagnosis of DiGeorge, velocardiofacial, conotruncal anomaly face syndromes share a common genetic cause, namely a 22q11.2 deletion [43–45]. The prevalence is 1 in 4000 to 6000 live births, but the severity of the phenotype is variable and in some the features may go unrecognized [46]. CHD are estimated to occur in 75–80% of patients with a 22q11.2 deletion. The most common CHDs associated with 22q11.2 deletion include tetralogy of Fallot (TOF) and aortic arch anomalies. Other conotruncal lesions include pulmonary atresia with ventricular septal defect (VSD), and truncus arteriosus [47, 48]. In cases of truncus arteriosus, the truncal valve tends to be

Identifying the cardiac patient with a 22q11.2 deletion early in life can provide substantial benefits to the child and family. Currently, it is recommended that infant with interrupted aortic arch type B, truncus arteriosus, TOF and isolated aortic arch anomalies undergo testing for a 22q11.2 deletion [22]. Prenatal diagnosis can be performed using FISH technology on samples obtained from chorionic villus sampling or amniocentesis if cardiac defects are present. Non-cardiac lesions are not easily diagnosed but, absent fetal thymus has been reported [50]. Many children initially present without cardiac symptoms in the form of recurrent infections. This may point to an underlying immunodeficiency associated with 22q11.2 deletion [51]. The risk of recurrence is in 50% as this is transmitted in an autosomal dominant inheritance if either parent carries the deletion. If neither parent carries the deletion, there may still

The CHARGE syndrome was previously referred as an association, however this was resolved after the discovery of causative mutations in chromodomain helicase DNA-binding gene7 (CHD7) on chromosome 8q12.1 [52, 53]. The phenotype is described by its acronym:

**conotruncal anomaly face syndrome)**

416 Congenital Anomalies - From the Embryo to the Neonate

**2.5. CHARGE syndrome**

more dysplastic when the 22q11 deletion is present [49].

be germline mosaicism, but the risk of recurrence is small (1%) [22, 48].

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 ventricle, TOF and dextrocardia [58].

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