Transforming growth factor-β receptor mutations and pulmonary arterial hypertension in childhood

Background - Pulmonary arterial hypertension (PAH) is a potentially fatal vasculopathy that can develop at any age. Adult-onset disease has previously been associated with mutations in BMPR2 and ALK-1. Presentation in early life may be associated with congenital heart disease but frequently is idiopathic. Methods and Results - We performed mutation analysis in genes encoding receptor members of the transforming growth factor-beta cell-signaling pathway in 18 children (age at presentation <6 years) with PAH. Sixteen children were initially diagnosed with idiopathic PAH and 2 with PAH in association with congenital heart defects. Germ-line mutations were observed in 4 patients (22%) ( age at disease onset, 1 month to 6 years), all of whom presented with idiopathic PAH. The BMPR2 mutations (n = 2, 11%) included a partial gene deletion and a nonsense mutation, both arising de novo in the proband. Importantly, a missense mutation of ALK-1 and a branch-site mutation of endoglin were also detected. Presenting clinical features or progression of pulmonary hypertension did not distinguish between patients with mutations in the different genes or between those without mutations. Conclusions - The cause of PAH presenting in childhood is heterogeneous in nature, with genetic defects of transforming growth factor-beta receptors playing a critical role.