Abstract
Pulmonary arterial hypertension (PAH; MIM 600799) is frequently associated with concomitant diseases, including congenital heart disease. 6% of patients with PAH show a family history of the disease [hereditary PAH (HPAH)], with the major genetic determinants of HPAH being heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR2). We present the case of a 38-year-old woman of Indian descent; initially admitted with progressive dyspnea [New York Heart Association (NYHA) class III]. The results of the proband’s clinical assessments are presented here. Cardiac catheterization confirmed idiopathic PAH with severe right ventricular hypertrophy associated with pulmonary arteriopathy. Initial treatment comprised the dual endothelin receptor antagonist, bosentan, furosemide, warfarin and intravenous infusion of prostaglandin I2 (PGI2) for 3 days. Despite this, the patient died of pulmonary hemorrhagic edema and cardiogenic shock after 6 days of intensive care. After relatives’ consent, post mortem assessments confirmed a diagnosis of PAH; the heart displayed significant right ventricular hypertrophy and it was particularly noted that the right atrial appendage had undergone extreme dilation. Pulmonary arteriopathy was characterized by medial hypertrophy, arterialization of muscular arteries and muscularization of non-muscularized distal arteries. Molecular genetic analyses revealed the presence of cis-mutations in the BMPR2 gene (p.Cys123Arg and p.Arg332X). Cosegregation studies were not available. Our findings suggest that mutations of the BMPR2 gene gave rise to the onset of PAH in this patient and that the severity of the onset and progression could be attributed to the presence of multiple mutations in a genedosage manner.