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.

Primary Hypertrophic Osteoarthropathy: An Update on Patient Features and Treatment

“…On the other hand, patients 3 and 4 exhibited delayed cranial suture closure that has led to the use of the term "cranio-osteoarthropathy". This has only been seen in patients with HPGD mutations 2,4,12,16 .…”

“…From the age of 12 years, "watch-glass" nails and digital clubbing started to develop (Supplementary Figure 1 available online at jrheum.org), associated with a worsening pachydermia and furrowing of the forehead, leading to the clinical suspicion of PHO. The diagnosis was supported by elevated prostaglandin E2 (PGE2) levels (Supplementary Table 1 available online at jrheum.org) and by sequencing HPGD, which identified 2 reported heterozygous mutations 2,4 (Table 1; Supplementary Figure 2 available online at jrheum.org). High-dose therapy with NSAID (ibuprofen 30 mg/kg/day) was started and is currently maintained, with clinical improvement but incomplete recovery.…”

“…However, for the pediatrician, who often has to contend with an incomplete clinical presentation 3 , diagnosis may be a challenge. The discovery of mutations in 2 prostaglandin pathway genes HPGD and SLCO2A1 has clarified the autosomal recessive inheritance [Mendelian Inheritance in Man (MIM) #259100, MIM #614441] of this genetically heterogeneous condition 4,5,6,7 .…”

Mesenchymal Hamartoma of the Liver: A Case Report

“…Most often, ectopic livers are found on the serosal surface of the gallbladder. In general, the reported sizes of the ectopic livers range from a few millimeters up to several centimetres [11,12]. The mesenchymal and epithelial hamartomas have been reported to arise from ectopic liver tissues .…”

Characterization of hypertrophic osteoarthropathy in an identified skeleton from Évora, Portugal, using combined and comparative morphology and microscopy

“…Only the secondary form is described in dogs. The primary form, also called pachyodermoperiostosis or Touraine-Solente-Golé syndrome, is a rare genetic disease that is inherited in an autosomal fashion (Latos-Bielenska et al, 2007), recently mapped to human chromosome 4q33-q34 and to gene mutations encoding 15-hydroxyprostangladin degradation (Uppal et al, 2008;Yao et al, 2009). This form, usually severe, affects primarily males (Aufderheide and Rodriguez-Martín, 1998), appears around the time of puberty, and its progression is limited to the puberal growth period (Christensen et al, 2013).…”