RAF1 mutation expands the cardiac phenotypic spectrum of Noonan syndrome: A case report.

Background: Noonan syndrome is a relatively common autosomal dominant genetic disorder characterized by cardiovascular defects owing to functional abnormalities in key genes such as RAF1. Mutations in RAF1 are typically associated with hypertrophic cardiomyopathy (HCM). However, in this case, the patient exhibited atrial and ventricular septal defects (VSDs).

Case summary: This case report describes an 11-year-old boy diagnosed with Noonan syndrome, in whom genetic testing revealed a c.770C>T (p.Ser257 Leu) mutation in RAF1. The patient presented with intermittent chest discomfort and shortness of breath, symptoms that significantly worsened after physical activity. Clinical evaluation revealed marked growth retardation and multiple physical abnormalities. Electrocardiographic and echocardiographic assessments revealed VSDs, atrial septal defects, and left ventricular outflow tract obstruction. Following multidisciplinary consultation, the patient underwent cardiac surgical intervention, which led to clinical improvement; however, they subsequently developed a third-degree atrioventricular block, necessitating the implantation of a permanent pacemaker. During follow-up, echocardiographic findings demonstrated near-complete resolution of the shunt across the atrial and ventricular septa, significant improvement in left ventricular outflow tract obstruction, and notable reduction in ventricular septal thickness. A genetic mutation at the c.770C>T (p.Ser257 Leu) locus of RAF1 is typically associated with HCM and pulmonary hypertension. However, this patient's clinical phenotype manifested as HCM, atrial septal defect, and VSD, suggesting that this mutation may involve a different pathophysiological mechanism.

Conclusion: This case confirms the genotype-phenotype heterogeneity of Noonan syndrome and highlights the complex management requirements of RAF1 mutation-associated cardiac pathologies. Early surgical intervention can ameliorate structural defects, but it must be integrated with genetic counseling and lifelong monitoring to optimize patient outcomes.