Cardiovascular Disease in the RASopathies

Cardiovascular disease is an important feature of the RASopathy disorders: Noonan, cardio-facio-cutaneous, and Costello syndromes with significant implications for short- and long-term morbidity and mortality. Moreover, cardiac disease is frequently a presenting feature that brings infants and children to the attention of genetics providers and often accelerates the process to obtaining a genetic diagnosis. Noonan syndrome and related RASopathies are unique in their strong predisposition for both congenital heart defects and acquired and progressive forms of cardiovascular disease, namely hypertrophic cardiomyopathy. While congenital defects, including pulmonary valve stenosis and hypertrophic cardiomyopathy were cardiac phenotypes that helped define these syndromes, it is now better appreciated that the cardiovascular phenotype is more complex, and that subtle cardiovascular features may be important contributors to long-term cardiovascular health, and provide clues about the role of the RAS/mitogen-activated protein kinase (MAPK) pathway in myocardial, valvular, and vascular biology and pathology. This chapter reviews what is known about common and less common cardiovascular phenotypes associated with RASopathies, with focus on genotype/phenotype correlations, treatments, and short- and long-term outcomes of medical and surgical treatments.