doi: 10.1161/01.CIR.0000153798.78540.87
(Circulation. 2005;111:435-441.)
© 2005 American Heart Association, Inc.
Hypertension |
Transforming Growth Factor-ß Receptor Mutations and Pulmonary Arterial Hypertension in Childhood
From the Division of Medical Genetics, University of Leicester, Leicester, UK (R.E.H., M.A.A., R.C.T.); Division of Paediatric Cardiology, Beatrix Children’s Hospital/University Hospital Groningen, Groningen, the Netherlands (R.B.); Vascular Biology and Pharmacology Unit, Institute of Child Health, UCL, London, UK (S.G.H.); Department of Paediatric Cardiology, Guy’s and St Thomas’ Hospital, London, UK (R.T.); Department of Paediatrics, Medical University Graz, Graz, Austria (C.J.M.); and Addenbrookes Hospital, University of Cambridge, Cambridge, UK (N.W.M.).
Correspondence to Richard C. Trembath, Professor of Medical Genetics, Departments of Genetics and Cardiovascular Sciences, Adrian Bldg, University of Leicester, Leicester LE1 7RH UK. E-mail rtrembat{at}hgmp.mrc.ac.uk
Received June 18, 2004; revision received September 17, 2004; accepted October 5, 2004.
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-ß 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-ß receptors playing a critical role.
Key Words: activin receptors, type I • receptors, growth factor • cell adhesion molecules • pulmonary heart disease • signal transduction
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