Bifid Cardiac Apex in Noonan Syndrome: An Unusual Cardiac Morphology Associated with a RAF1 Pathogenic Variant.

In this report, we describe the case of a 4-month-old infant diagnosed after birth with severe pulmonary stenosis and Noonan syndrome (NS) carrying a heterozygous pathogenic variant in the RAF1 gene. The patient was admitted for surgical correction, and during preoperative evaluation, severe biventricular hypertrophic cardiomyopathy, severe valvular pulmonary stenosis, and a bifid cardiac apex (BCA) were identified. The surgical procedure was performed without complications; however, due to postoperative hemodynamic instability, extracorporeal membrane oxygenation (ECMO) support was initiated. The patient initially showed satisfactory clinical evolution, allowing ECMO weaning; nevertheless, the patient subsequently developed cardiac arrest and died. It is known that the right ventricle and left ventricle develop independently and later fuse during embryogenesis. Disruption of this developmental process may result in a bifid apex. The GTPase Rac1 plays a regulatory role in embryonic cardiac development and cardiomyocyte differentiation. Cardiomyocyte-specific deletion of Rac1 (Rac1^Nkx2.5^) during cardiac development has been shown to result in a bifid apex, in addition to hypertrabeculation and a thin compact myocardium. NS caused by RAF1 mutations, as observed in this case, is associated with cardiac malformations in approximately 5%-10% of cases. Hypertrophic cardiomyopathy has an incidence of up to 95%, which may significantly worsen prognosis. Although this morphological finding is rare, when isolated it is usually associated with a favorable prognosis. However, BCA has been described in association with congenital heart disease, requiring careful evaluation. When associated with congenital cardiac malformations and genetic syndromes, particularly hypertrophic cardiomyopathy, the prognosis may be guarded.