The majority of congenital heart defects (CHDs) occur as isolated malformations, whereas approximately 25% to 30% of them are associated with extracardiac anomalies, in the setting of large or submicroscopic chromosomal anomalies, monogenic mendelian disorders, and genetic associations.1 Furthermore, recent studies reported a higher frequency (approximately 40%) of detecting an underlying disorder when the cohort studies were done on patients with cardiac defects requiring invasive or surgical interventions (i.e., the most severe forms).2 Moreover, although in neonates with cardiac defect the incidence of aneuploidy ranges between 9% and 18%, among fetuses with prenatally diagnosed heart malformation the incidence of aneuploidy is higher, ranging between 33% and 42%.3 Almost all (98%) fetuses with aneuploidy and cardiac defect have one or more extracardiac malformation.3 The strong association between CHD and genetic syndromes may be explained by the important contribution of extracardiac tissues to accomplish a normal heart development This observation, made by Maria Victoria de la Cruz in 1977,4 was confirmed by the discovery of a second heart field contributing to the formation of outflow tract and the venous pole of the heart So, it does not come as a surprise that in the presence of a genetic syndrome, which involves multiple organs, the contribution of the extracardiac tissues required for heart development also can be missing, causing an associated CHD Neurodevelopmental anomalies are one of the most important problems in children with CHD These complications affect approximately 10% of children with cardiac defect and about 50% of the group with severe heart malformation5 is prevalently in patients with associated genetic syndromes.6 Some types of CHD, such as atrioventricular canal defect (AVCD) and conotruncal malformations, are more frequently found in association with genetic syndromes such as Down or deletion 22q11.2 syndromes, whereas other types are prevalently isolated defects (tricuspid atresia)1,7 (Table 77.1) Nevertheless, all types of CHDs need to be evaluated by a clinical geneticist Specific genetic testing should be indicated in patients with extracardiac anomalies or familial recurrence of the disease Knowledge in this area is evolving dramatically, and advances in molecular testing are leading to the identification of an increased number of causes of syndromic and isolated CHDs Table 77.1 Prevalence of Extracardiac Anomalies in the Setting of Genetic Syndromes in Different Types of Congenital Heart Defects Congenital Heart Defect Atrioventricular canal defect Interrupted aortic arch Truncus arteriosus Double-outlet right ventricle Atrial septal defect Tetralogy of Fallot Aortic coarctation Abnormal pulmonary venous return Ventricular septal defect Ebstein anomaly Pulmonary stenosis Aortic stenosis Hypoplastic left ventricle Tricuspid atresia Transposition of the great arteries Pulmonary atresia and intact septum Frequency (%) 70–80 40–50 40–45 35–40 30–40 30–35 23–25 20–23 18–25 18–23 15–25 15–20 15–20 12–18 10–12 8–12 Historically, the care of CHDs associated with genetic syndromes has been set aside because of their complexity, resulting in an increased risk for death and/or major complications.8 The improvement in surgical repair of even the most challenging CHDs allowed the survival of these patients, switching our perspective from an exclusively cardiac outcome to a multispecialty approach, where the general well-being of a child with CHD and genetic syndromes is our main goal.9 Several phenotype-genotype correlation studies suggest that specific morphogenetic mechanisms put in motion by genes can result in a specific cardiac phenotype.10 These results have several important clinical implications In fact, the recognition of distinct cardiac anatomic subtypes may help in suggesting accurate diagnoses and specific medical and surgical therapy.9 A special effort needs to be made for the identification of specific syndromes because this has a dramatic impact on management, surgical outcomes, longterm outlook, and genetic counseling for future pregnancies A multidisciplinary approach, with focus on the specific risk factors related to specific genetic syndromes, can be used in the patients’ treatment and follow-up Beside the clinical implications, the genotype-phenotype correlation shed light on embryologic mechanisms that control cardiac development, increasing our knowledge on the genetic basis of CHD also in nonsyndromic patients.11 Chromosomal Anomalies Down Syndrome Clinical Features Down syndrome is characterized by neonatal hypotonia, developmental and cognitive delay, cardiac and gastrointestinal malformations, and specific facial anomalies, including flat face, upslanting palpebral fissures, epicanthal folds, small nose with low nasal bridge, and downturned small mouth with tendency to protrude the tongue (Fig 77.1) Associated gastrointestinal malformation include duodenal atresia, Hirschsprung disease, anal atresia, or stenosis (Table 77.2) Additional medical complications can manifest as thyroid gland malfunctioning, upper respiratory infections, audiologic problems, or hematologic diseases.12 FIG 77.1 Facial appearance of Down syndrome