CASE REPORT Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension

P ulmonary arterial hypertension (PAH) is defined as a group of diseases characterised by a progressive increase in pulmonary vascular resistance leading to right heart failure and ultimately to death. Familial cases segregate as an autosomal dominant trait with low disease gene penetrance. Mutations within the bone morphogenetic protein receptor type II gene (BMPR2), coding for a receptor of the transforming growth factor b (TGF-b) superfamily, have been shown to underlie most familial cases of primary pulmonary hypertension 3 and at least 26% of so-called ‘‘sporadic’’ cases. Pulmonary arterial hypertension can also develop in patients with various associated conditions including hereditary haemorrhagic telangiectasia or exposure to anorectic agents such as fenfluramine derivatives. The frequency of PAH is evaluated at one in 10 000 to one in 100 000 patients with a history of fenfluramine derivatives intake. Conversely, since BMPR2 mutations have been detected in 9% of patients with fenfluramine or dexfenfluramine associated PAH, associated environmental, epigenetic or genetic factors are required for the development of PAH. Mutations in two genes encoding TGF-b receptors (activin receptor-like kinase 1 (ALK1) and endoglin) underlie hereditary haemorrhagic telangiectasia, an autosomal dominant vascular dysplasia with abnormally dilated vessels forming mucosal and visceral telangiectasia. Approximately 25% of families affected in France and in the UK carry a known endoglin germline mutation. Trembath and colleagues recently described cases of PAH in families affected by hereditary haemorrhagic telangiectasia and mutations of ALK1 were identified in these subjects. We describe a case of dexfenfluramine associated PAH occurring in a patient with hereditary haemorrhagic telangiectasia related to a mutation within the endoglin gene. This report highlights the critical role of the TGF-b signalling pathway in this condition.