Natural history and predictors of all-cause mortality and major arrhythmic cardiac events in pediatric RASopathy associated hypertrophic cardiomyopathy

Abstract The RASopathies are a group of developmental disorders caused by germline variants in components of the RAS-MAPK pathway, commonly associated with hypertrophic cardiomyopathy (HCM). The aim of this study was to describe the natural history and predictors of all-cause mortality and major arrhythmic cardiac events (MACE) in a large, multi-centre cohort of paediatric patients with a RASopathy syndrome and HCM. One-hundred-and-forty-nine patients were included (111 (74.5%) Noonan Syndrome (NS); 12 (8.05%) Noonan Syndrome with Multiple Lentigines (NSML); 6 (4.03%) Costello Syndrome (CS); 6 (4.03%) Cardiofaciocutaneous Syndrome (CFCS); and 14 (9.4%) with Noonan-like syndrome patients). NSML patients had higher maximal left ventricular wall thickness (MLVWT) (z score 17.02 (10.57-32.78), p=0.004] and higher left ventricular outflow tract (LVOT) gradient values (60mmHg, 36-80, p=0.019), with no other significant echocardiographic differences between RASopathy syndromes. Over a median follow up of 197.5 months (93.58-370), 23 patients (15.43%) died, at a median age of 48.94 months (3.29-175.84). Overall survival was 96.45% (91.69-98.51), 90.42% (84.04-94.33) and 84.12 (75.42-89.94) at 1, 5 and 10 years, respectively, but this was varied according to RASopathy syndrome. RASopathy syndrome, specifically Noonan-like syndrome (Hazard ratio 4.18, p=0.032) and congestive cardiac failure admission (Hazard ratio 7.35, p=0.037) were independent predictors of all-cause mortality and LVOT gradient was an independent predictor for MACE (Hazard ratio 1.02, p=0.025). These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify predictors of adverse outcome in patients with RASopathy-related HCM.