Structural diseases of the heart: syndromes affecting the cardiovascular system

Congenital heart disease (CHD) occurs in association with extracardiac anomalies or as part of an identified syndrome in 25–40% of cases. Approximately 30% of children with a chromosomal abnormality have CHD. Aneuploidy, or abnormal chromosomal number, accounts for a significant proportion of CHD. Of individuals born with trisomy 21, 50% have CHD, the most common being an atrioventricular septal defect (45%). In segmental aneuploidies, the so-called microdeletion syndromes, small submicroscopic chromosomal deletions can lead to CHD. The 22q11 deletion syndrome causes CHD with thymic and parathyroid hypoplasia (DiGeorge syndrome) and characteristic dysmorphic craniofacial features due to abnormal pharyngeal arch development. Williams–Beuren syndrome with renovascular anomalies, typical elfin facies, and neurological deficits, is characterized by cardiac involvement in the form of supravalvar aortic and peripheral pulmonic stenosis. Chromosome 1p36 deletion syndrome is the most common subterminal deletion syndrome. A substantial proportion of individuals with 1p36 deletion syndrome have CHD which may occur in the presence or absence of cardiomyopathy, most commonly left ventricular non-compaction cardiomyopathy. Single gene mutations may also cause syndromic CHD. Noonan syndrome and related disorders (‘RASopathies’) are caused by dominant gain-of-function mutations in one of the genes which encode proteins that function in the Ras/mitogen-activated protein kinase (RAS-MAPK) signal transduction pathway. Holt–Oram syndrome is associated with mutations in the transcription factor TBX5. Alagille syndrome is caused by mutations in JAG1, a gene encoding a ligand in the Notch signaling pathway. Heterotaxy syndrome, which means randomization of cardiac, pulmonary, or gastrointestinal situs, is frequently associated with CHD.