title: Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy.
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.
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Uppal
authors.forename: Christine P
authors.initials: CP
authors.lastname: Diggle
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.forename: Gamal H
authors.initials: GH
authors.lastname: Ibrahim
authors.forename: Philip S
authors.initials: PS
authors.lastname: Helliwell
authors.forename: Anna
authors.initials: A
authors.lastname: Latos-Bieleńska
authors.forename: Simon E V
authors.initials: SE
authors.lastname: Phillips
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Bennett
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D003241:Consanguinity; D015232:Dinoprostone / Q000652:urine; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D015894:Genome, Human; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010004:Osteoarthropathy, Primary Hypertrophic / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D010375:Pedigree; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D011994:Recombinant Proteins; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone