Genetic, clinical, diagnostic and therapeutic profile in patients with Noonan Syndrome, RASopathies and Hypertrophic Cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease, characterized by an unexplained left ventricular hypertrophy (LVH). RASopathies are relatively rare genetic diseases that can also cause LVH, but despite the similar cardiac phenotypic presentation, literature to date is scarce regarding the clinical evolution of RASopathies. Purpose To evaluate clinical, electrocardiographic, echocardiographic profiles and outcomes, including the need for septal reduction therapies in patients with RASopathies and significant LVH from a database extracted from medical records. Methods This was a single center, observational, retrospective and descriptive study based on the analysis of electronic medical records from January 1997 to January 2024. Patients with a diagnosis confirmed by genetic testing or clinical criteria of Noonan Syndrome (NS) or RASopathies and significant LVH were included. Results Thirty nine patients were evaluated. Mos patients were male (56%) and were diagnosed with NS (80%) and NS with multiple lentigines (18%). The most frequent mutations were PTPN11 (43.7%) and RAF1 (25%). The most common systemic findings were facial changes (78%) and short stature/growth retardation (62%), followed by skin (30%) and orthopedic (30%) lesions. Mitral valve abnormalities (MV) were the most frequent association with significant LVH (46.2%), followed by pulmonary stenosis (28.2%) and atrial septal defect (20.5%). Most patients was in Functional Class NYHA 1 (43.6%) and 2 (46.2%) and on beta blockers (69.2%). On echocardiography, patients presented normal left ventricular (LV) ejection fraction and most patients presented LV outflow tract obstruction (56%). Systolic anterior motion of the MV was described in 40% of the patients. On EKG, most patients were in sinus rhythm (58.5%) and evidenced signs of LVH (71.4%). Only 4% of the patients developed atrial fibrillation and 12,5% required definitive pacemaker. Nine (23.1%) patients had at least one of the following outcomes: heart transplantation, myectomy, sudden recovered death, need for ICD and death. A multivariate analysis was performed and only age at diagnosis of LVH showed a significant association with composite outcomes. Conclusions In this study, patients with RASopathies and LVH had an earlier age at diagnosis, higher percentage of LVOT obstruction, MV abnormalities, and a higher occurrence of outcomes when compared to the HCM cohort of the same institution, suggesting a more severe clinical picture despite the similar phenotype.