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Eur Respir J 2002; 20:518-523
Copyright ©ERS Journals Ltd 2002

BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives

M. Humbert1, Z. Deng2,6, G. Simonneau1, R.J. Barst3,5, O. Sitbon1, M. Wolf4, N. Cuervo2, K.J. Moore2, S.E. Hodge2,6,7, J.A. Knowles2,6 and J.H. Morse3

1 Service de Pneumologie, and 4 Hématologie, Hôpital Antoine Béclère, Clamart, France, and the Depts of 3 Medicine, 5 Pediatrics, and 2 Psychiatry, Columbia University College of Physicians and Surgeons, 6 New York State Psychiatric Institute, and 7 Division of Biostatistics, Columbia University School of Public Health, New York, NY, USA

CORRESPONDENCE: J.H. Morse, Dept of Medicine, Columbia Presbyterian Medical Center, PH 8 East, Suite 101, 630 West 168th Street, New York, NY, 10032. Fax: 212 3054943. E-mail: jhm4@columbia.edu

Keywords: anorexigens, bone morphogenetic receptor 2, fenfluramine, pulmonary hypertension

Received: March 1, 2002
Accepted May 22, 2002

This study was supported by grants from NIH-HBLI-60056, NIH-DK-31813, INSERM, AFM, and Université Paris-Sud. Z. Deng was supported by a PHA fellowship award.

This study investigated whether patients developing pulmonary arterial hypertension (PAH) after exposure to the appetite suppressants fenfluramine and dexfenfluramine have mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene, as reported in primary pulmonary hypertension.

BMPR2 was examined for mutations in 33 unrelated patients with sporadic PAH, and in two sisters with PAH, all of whom had taken fenfluramine derivatives, as well as in 130 normal controls. The PAH patients also underwent cardiac catheterisation and body mass determinations.

Three BMPR2 mutations predicting changes in the primary structure of the BMPR-II protein were found in three of the 33 unrelated patients (9%), and a fourth mutation was found in the two sisters. No BMPR2 mutations were identified in the 130 normal controls. This difference in frequency was statistically significant. Moreover, the mutation-positive patients had a somewhat shorter duration of fenfluramine exposure before illness than the mutation-negative patients, a difference that was statistically significant when the two sisters were included in the analysis.

In conclusion, the present authors have detected bone morphogenetic protein receptor 2 mutations that appear to be rare in the general population but may combine with exposure to fenfluramine derivatives to greatly increase the risk of developing severe pulmonary arterial hypertension.




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