Cardiovascular disease in Noonan syndrome

Background Noonan syndrome (NS), a relatively common autosomal dominant disorder with an incidence of 1 in 1000 to 2500 live births, is the most common syndromic cause of congenital heart disease after Trisomy 21. Objective To comprehensively define the spectrum of cardiac morphology and specific clinical course of a large cohort of NS patients. Design Retrospective, descriptive case series study. Patients An international Harvard-based NS registry was combined with clinical data from NS patients followed at Boston Children's Hospital, Massachusetts, USA. Results We identified 293 patients with NS. Cardiovascular disease was seen in 81% (n=237) including pulmonary stenosis in 57%, secundum atrial septal defects in 32% and hypertrophic cardiomyopathy in 16%. A genetic mutation of the RAS-MAPK signalling pathway was identified in 62% (n=136). Genotype-phenotype associations were noted between PTPN11 mutations and atrial septal defects (p=0.001), and pulmonary stenosis (p<0.001). RAF1 mutations were associated with hypertrophic cardiomyopathy (p<0.001). Cardiovascular outcomes that differed specifically in a NS cohort included high re-intervention rates (65%) after percutaneous balloon pulmonary valvuloplasty for valvar pulmonary stenosis. Additionally, in NS patients with hypertrophic cardiomyopathy, a clinically significant regression of hypertrophy (17%) was observed as was a markedly higher incidence of concomitant congenital heart defects (70%). Conclusions Patients with NS have a distinct spectrum of cardiac phenotypes that may have a natural history and response to therapy atypical to that normally seen in non-syndromic heart disease. A diagnosis of NS in a patient with pulmonary stenosis or infant-onset hypertrophic cardiomyopathy would facilitate condition-specific counselling on outcome and prognosis.