The Heart in Ras-MAPK Pathway Disorders

Abstract

Noonan syndrome (NS) and related disorders are due to mutations in the genes of the Ras-MAPK pathway. Congenital heart defect (CHD) is diagnosed in 60–85% of patients affected by these conditions. Pulmonary valve stenosis (PVS) and hypertrophic cardiomyopathy (HCM) are the most common defects. Nevertheless, the spectrum of cardiac malformations has been progressively widened, including also atrioventricular canal defect (AVCD), mitral valve anomalies (MVA), atrial septal defect (ASD), aortic coarctation (AC), and other defects. The anatomic pattern of CHDs in NS and related disorders is specific. PVS has dysplastic pulmonary valve and fibrous thickening of the annulus and the leaflets, while HCM is characterized by left ventricle hypertrophy with asymmetric septal thickening and frequent systolic anterior motion of the mitral valve. The prevalence of specific CHDs in the different clinical conditions is varying depending on the mutated gene, and at time also on the different allelic mutations. Particularly, PVS is the prevalent CHD in NS due to <i>PTPN11</i> mutations, while HCM is the predominant cardiac manifestation of NS patients with <i>RAF1</i> mutations and LS patients with <i>PTPN11</i> mutation.