Phenotype progression in pediatric RASopathy-associated hypertrophic cardiomyopathy

Abstract

Abstract Background RASopathy syndromes represent the second most common cause of hypertrophic cardiomyopathy (HCM) in children. RASopathy associated HCM (Ras-HCM) has been shown to differ both in cardiac phenotype and long-term outcomes from sarcomeric HCM. However, there is a lack of knowledge from large cohort studies of how the cardiac phenotype of Ras-HCM changes over time. Aim To describe cardiac phenotype changes over time in children with Ras-HCM Methods Retrospective data from 148 patients diagnosed with Ras-HCM aged <18 years with ³2 follow-up visits were included. Clinical and echocardiographic data were collected at baseline assessment, 1, 2, and 5 years of follow up. Separate analyses were performed for patients who survived, versus patients who died or had a heart transplant (censoring events). Results One-hundred-and-two (68.9%) patients with Noonan syndrome, 25 (16.9%) with Noonan-syndrome with multiple lentigines, 10 (6.8%) with Costello syndrome, 9 (6.1%) with cardio-facio-cutaneous syndrome and 2 (1.4%) patients with Noonan-like syndrome with a median age of diagnosis 0.16 years (0.01-0.89) were seen at a median baseline age of 1.41 years (0.37-5.71) and followed up for a median of 12.1 years (4.8-17.4). During follow up, 18 patients (12.2%) died at a median age of 1.8 years (0.5-8.7) and 17 (12.5%) had a left ventricular myectomy, at a median age of 7.0 years (3.1-12.7). At baseline evaluation, patients who died compared to those who survived had a lower median age [0.4 years (0.1-0.8) versus 2.3 years (0.5-7.6), p<0.001], a higher proportion of them had a NYHA class>I (54.5% vs 15.1%, p<0.001), a higher maximal left ventricular wall thickness (MLVWT) z-score [13.4 (7.5) vs 9.6 (6.2), p=0.04], a higher proportion of left ventricular outflow tract obstruction (LVOTO) [64.7% vs 43.8%, p=0.087] and a higher proportion of biventricular hypertrophy [75% vs 49.2%, p=0.045]. For survivors, the MLVWT z-score improved over follow up [+9.6(6.2) at baseline vs. +7.9(5.5) at 5 years, p=0.072], and the proportion of patients with LVOTO (43.8% at baseline vs. 27.9% at 5 years, p=0.019) and biventricular hypertrophy (49.2% at baseline vs. 35.5% at 5 years, p=0.012) decreased over follow up. Conclusion While at baseline evaluation Ras-HCM has a high burden of symptoms, biventricular hypertrophy and LVOTO for patients who die or have a heart transplant, we have demonstrated that for survivors, over follow up, the phenotype becomes milder.Table 1