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Published on: August 8, 2022
Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy
Olga Boleti1,2, Gabrielle Norrish1,2, Ella Field1,2
1Centre for Inherited Cardiovascular Diseases, Department of Cardiology, Great Ormond Street Hospital, London, UK.
Insights
Children with RASopathy syndromes and hypertrophic cardiomyopathy (HCM) have a distinct survival rate that varies by syndrome. Congestive cardiac failure and non-sustained ventricular tachycardia predict mortality in these pediatric patients.
Area of Science:
- Pediatric Cardiology
- Genetics
- Cardiovascular Research
Background:
- RASopathy syndromes are genetic disorders associated with various clinical features, including cardiac abnormalities.
- Hypertrophic cardiomyopathy (HCM) is a common cardiac manifestation in children with RASopathies, impacting their long-term health.
- Understanding the natural history and mortality predictors in this specific population is crucial for clinical management.
Purpose of the Study:
- To describe the natural history of RASopathy-related HCM in children.
- To identify predictors of all-cause mortality and sudden cardiac death (SCD) or equivalent events.
- To compare outcomes across different RASopathy syndromes.
Main Methods:
- Retrospective cohort study involving 14 pediatric cardiology centers in the UK and Ireland.
- Included children under 18 years with HCM and a RASopathy diagnosis (Noonan syndrome, NSML, Costello, CFCS, NS-LAH).
- Analyzed survival data and identified mortality predictors using univariate analysis.
Main Results:
- 149 patients were recruited; Noonan syndrome was most common (74.5%).
- Over a median follow-up of 197.5 months, 15.43% of patients died.
- Survival varied by RASopathy syndrome, with Noonan-like syndrome showing worse survival despite a milder HCM phenotype.
- Congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and LVOT gradient were significant predictors of mortality or SCD/equivalent events.
Conclusions:
- RASopathy-related HCM represents a unique patient group with variable prognoses.
- Noonan-like syndrome patients have a distinct phenotype with poorer survival outcomes.
- Identifying predictors like CCF, NSVT, and LVOT gradient aids in risk stratification and management of pediatric patients with RASopathy-related HCM.
Aims:
This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM).
Methods And Results:
This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P = 0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event.
Conclusions:
These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.
