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      Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy.

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          Abstract

          Digital clubbing, recognized by Hippocrates in the fifth century BC, is the outward hallmark of pulmonary hypertrophic osteoarthropathy, a clinical constellation that develops secondary to various acquired diseases, especially intrathoracic neoplasm. The pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of hypertrophic osteoarthropathy (PHO) is recognized. This familial disorder can cause diagnostic confusion, as well as significant disability. By autozygosity methods, we mapped PHO to chromosome 4q33-q34 and identified mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation. Homozygous individuals develop PHO secondary to chronically elevated prostaglandin E(2) levels. Heterozygous relatives also show milder biochemical and clinical manifestations. These findings not only suggest therapies for PHO, but also imply that clubbing secondary to other pathologies may be prostaglandin mediated. Testing for HPGD mutations and biochemical testing for HPGD deficiency in patients with unexplained clubbing might help to obviate extensive searches for occult pathology.

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          Author and article information

          Journal
          Nat Genet
          Nature genetics
          Springer Science and Business Media LLC
          1546-1718
          1061-4036
          Jun 2008
          : 40
          : 6
          Affiliations
          [1 ] Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
          Article
          ng.153
          10.1038/ng.153
          18500342
          ebdf0dbc-aff4-40b8-8034-42baa26404f5
          History

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