Abstract 4371492: When Genes Collide: Hypertrophic Cardiomyopathy and Neurofibromatosis Type 1

Abstract

Background: Hypertrophic cardiomyopathy (HCM) links to mutations in sarcomeric genes; however, evidence indicates overlap with RASopathies, particularly Neurofibromatosis Type 1 (NF1). Mutations in NF1 result in impaired neurofibromin function, disrupting RAS/MAPK signaling pathways and predisposing individuals to cutaneous and cardiovascular abnormalities. Description of Case: A 30-year-old South Asian male presented with exertional chest pain and dyspnea, classified as New York Heart Association (NYHA) Class II. Clinical examination revealed multiple cutaneous neurofibromas, indicative of NF1. Electrocardiography (ECG) demonstrated left ventricular hypertrophy, while echocardiography confirmed the presence of asymmetric septal hypertrophy and systolic anterior motion (SAM) of the mitral valve, findings consistent with hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction. Laboratory investigations revealed severe iron-deficiency anemia, attributed to alcohol-related malnutrition. Familial screening indicated that his mother and sister, both positive for NF1, also exhibited asymptomatic HCM on echocardiography. This familial clustering underscored the syndromic nature of his condition. The patient was initiated on guideline-directed medical therapy, alongside lifestyle interventions targeting anemia and alcohol cessation. Discussion: This case illustrates HCM with NF1, a RASopathy not typically in cardiomyopathy evaluations. The structural phenotype included SAM and left ventricular outflow tract (LVOT) obstruction, more common in syndromic than sarcomeric HCM. The interplay between genetic predisposition, systemic comorbidities like anemia and malnutrition, and cardiac morphology contributed to symptoms and disease progression. Familial clustering highlights the need for genetic counseling and echocardiographic screening in first-degree relatives. Additionally, emerging molecular therapies targeting RAS/MAPK pathway dysregulation may offer future therapeutic options for RASopathy-related HCM. Conclusion: The management of syndromic HCM in the context of NF1 necessitates a multidisciplinary approach. This case underscores the critical role of genetic evaluation, family screening, and systemic optimization in the treatment of non-sarcomeric HCM. Increased awareness of such associations can facilitate early diagnosis and enable the customization of therapeutic strategies in genetically complex cardiac conditions.