Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis

Abstract

Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E(2) (PGE(2)) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE(2), but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE(2) metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity.

Autoinflammatory bone disorders

“…Homozygous mutations in the 15-hydroxyprostaglandin dehydrogenase (HPGD) gene, encoding the major enzyme responsible for prostaglandin degradation, or the solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene, which encodes a prostaglandin transporter protein (PGT) responsible for intracellular prostaglandin up-take, have been identified as underlying cause [88][89][90][91][92][93][94][95]. Increased levels of circulating PGE 2 in PHO patients together with the observation, that infused PGE 2 (for therapeutic reasons in treating newborns with duct-dependent congenital heart disease) can induce skeletal changes similar to PHO, suggest that increased availability of systemic PGE 2 is responsible for the symptoms observed in PHO patients [88,91,96].…”

Primary Hypertrophic Osteoarthropathy: An Update on Patient Features and Treatment

“…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 .…”

“…Patient 1 developed initial symptoms much earlier than patient 2. The onset of PHO is usually before the age of 20, but its biphasic incidence is now attributed to the genetic heterogeneity, with onset of symptoms in early childhood for HPGD patients and during puberty/early adulthood for SLCO2A1 patients 5,6,9,10,11,12,13 .…”

“…The Journal of on May 12, 2018 -Published by www.jrheum.org Downloaded from described as having more severe symptoms overall 6,9,11 , the presence of skin folds (as cutis verticis gyrata) 5,12 , and chronic anemia and/or pancytopenia, secondary to hypocellular myelofibrosis 5,14,15 . On the other hand, patients 3 and 4 exhibited delayed cranial suture closure that has led to the use of the term "cranio-osteoarthropathy".…”

“…Nevertheless, a patient with JIA, nonresponder to DMARD and biological therapies, and with a better response to NSAID, should be considered as having another disease and investigated for further clinical signs. Indeed, HPGD and SLCO2A1 patients usually experience some positive effects on joint pain and swelling while being treated with NSAID 5,12,16,17,18 , but it is uncertain if either the use of indomethacin compared with ibuprofen could provide better results clinically, as for patient 3, or if the phenotype of this patient is milder as a consequence of being female.…”