Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy.
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.
Uppal
Sandeep
S
Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Diggle
Christine P
CP
Carr
Ian M
IM
Fishwick
Colin W G
CW
Ahmed
Mushtaq
M
Ibrahim
Gamal H
GH
Helliwell
Philip S
PS
Latos-Bieleńska
Anna
A
Phillips
Simon E V
SE
Markham
Alexander F
AF
Bennett
Christopher P
CP
Bonthron
David T
DT
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
D011994:Recombinant Proteins; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone