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Bone Morphogenetic Protein Receptor 2 Mutations in Adults and Children With Idiopathic Pulmonary Arterial Hypertension : Association With Thyroid Disease* FREE TO VIEW

Kari E. Roberts, MD; Robyn J. Barst, MD, FCCP; Jude J. McElroy, AB; Allison Widlitz, PA; Kiran Chada, PhD; James A. Knowles, MD, PhD; Jane H. Morse, MD
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*From the Departments of Medicine (Drs. Roberts and Morse), Pediatrics (Dr. Barst and Ms. Widlitz), and Psychiatry (Mr. McElroy and Dr. Knowles), Columbia University College of Physicians and Surgeons, New York, NY; and the Department of Biochemistry (Dr. Chada), Robert Wood Johnson Medical School, Piscataway, NJ.

Correspondence to James A. Knowles, MD, PhD, New York State Psychiatric Institute, Unit 28, Room 5916, 1051 Riverside Dr, New York, NY 10032; e-mail: jak8@columbia.edu

Chest. 2005;128(6_suppl):618S. doi:10.1378/chest.128.6_suppl.618S
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Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) and activin receptor-like kinase 1, both members of the transforming growth factor-β family, have been reported in pulmonary arterial hypertension. The primary aim of the study was to determine the frequency of BMPR2 mutations in 75 children and 66 adults with idiopathic pulmonary arterial hypertension (IPAH). Our secondary aim was to ascertain whether clinical parameters such as thyroid disease and antinuclear antibodies defined the mutation-positive patients. Clinical evaluation consisted of right heart catheterization, evaluation of thyroid function, and serologic determinations of ANAs and specific autoantibodies related to connective tissue diseases. Exonic BMPR2 mutations were determined by nucleic acid sequencing.

Five novel exonic BMPR2 mutations were found in 4 of 66 adults (6%) and in 1 of 75 children (1%) with IPAH. The four adults had two frameshift mutations (exons 9 and 12) and two nonsense mutations (exons 2 and 9), whereas the child had an exon 9 missense mutation. Remarkably, all five BMPR2 mutation-positive patients had thyroid disease (100%; but two cases are still being reviewed), but it was present in only 24% of the adults and 5% of the children without mutations. Three of the adults and the child had thyroiditis, and one had adult follicular hyperplasia. A high titer of antimicrosomal antibodies was present in the child and an adult with thyroiditis. All of the BMPR2 mutation-positive adults were antinuclear antibody+ but lacked autoantibodies characteristic of a specific connective tissue disease.

BMPR2 mutations were found in a minority of adults and in even fewer children with IPAH. Remaining to be investigated are whether the children have a different disease from adults, the confirmation of the association between the presence of thyroid disease and mutations in BMPR2, and if valid, the reason for this interesting association.

Abbreviations: BMPR2 = bone morphogenetic protein receptor type 2; IPAH = idiopathic pulmonary arterial hypertension




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