Clinical characteristics and etiology-specific outcome in pediatric hypertrophic cardiomyopathy

Abstract

Introduction: Childhood-onset cardiomyopathies are rare disease (incidence 1/100,000) presenting with diverse, potentially severe phenotypes. The etiologies range from idiopathic/sarcomeric forms to syndromic diseases, neuromuscular disorders, and inborn errors of metabolism, but cause-specific outcomes remain incompletely understood. This study analyzed the clinical course of a large cohort of children with hypertrophic cardiomyopathy (HCM), stratified by etiology.

Methods: Patients clinically diagnosed with HCM before 18 years of age at Heidelberg University Hospital, Germany (2000-2024) were included (n = 146). The clinical data were compiled by the Medical Data Integration Center and supplemented by manual data extraction. Outcomes included survival, myectomy, ICD and PPM implantation, arrhythmias, heart transplantation, cardiac arrest, and echocardiographic features at first presentation.

Results: Of 146 patients, 31.5% (n = 46) were followed into adulthood. HCM etiologies included idiopathic/sarcomeric (37%, n = 54), inborn errors of metabolism (21.2%, n = 31), RASopathy (15.7%, n = 23), neuromuscular disorders (6.8%, n = 10), other syndromic (6.2%, n = 9), and other (13%, n = 19). Diagnosis was made in infancy (< 1 year) (47.3%, n = 69), childhood (1-18 years) (40.4%, n = 59), or was confirmed before age 18 without specific timing available (12.3%, n = 18). Early diagnosis correlated with syndromic and multisystem disease. The echocardiographic findings and clinical outcomes varied by etiology. During a mean follow-up of 13.6 ± 10.5 years, 11% (n = 16) died, with 62.5% (n = 10) of deaths occurring within the first two years of life. Survival was highest in idiopathic/sarcomeric HCM (96.7%) and lower in neuromuscular (85.7%), syndromic (76.2%), inborn errors of metabolism (70.5%), RASopathy (57.8%), and other forms (54.2%). Death frequently involved non-cardiovascular causes. Infants had higher early mortality, which normalized among those surviving beyond two years. In idiopathic/sarcomeric HCM, outcomes did not differ between those diagnosed in infancy versus later childhood. Reduced ejection fraction and elevated NT-proBNP levels were predictive of mortality, while the use of Class IV anti-arrhythmics was associated with improved survival.

Conclusions: The results of this analysis show significant variability of outcomes by HCM subtype in children. Idiopathic/sarcomeric and neuromuscular disease-associated HCM had the best prognosis, while other non-idiopathic/non-sarcomeric forms of HCM showed worse outcomes. Pediatric HCM presents with diverse underlying causes, unique phenotypes, and clinical trajectories, requiring tailored treatment approaches.

Keywords: Cardiomegaly; Genetic diseases; Hypertrophic cardiomyopathy; Inborn; Pediatrics; Rare diseases.