SLCO2A1 – Primary Hypertrophic Osteoarthropathy

Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis, is a rare autosomal recessive disorder characterized by digital clubbing, periostosis, and pachydermia. Mutations in the prostaglandin transporter gene SLCO2A1 underlie the PHOAR2 subtype of Primary Hypertrophic Osteoarthropathy, with over 100 unrelated probands across >20 families reported to date ([PMID:22197487]; [PMID:22906430]; [PMID:28425581]).

Inheritance is autosomal recessive, with both homozygous and compound heterozygous SLCO2A1 variants identified. In a Chinese cohort of 43 PHO patients, 36 carried biallelic SLCO2A1 mutations, confirming consistent segregation of LoF alleles ([PMID:28425581]).

The SLCO2A1 variant spectrum includes splice-site (c.940+1G>A), nonsense, frameshift, and missense alleles. A heterozygous missense change c.656C>T (p.Pro219Leu) was reported in a Chinese patient demonstrating classic PHO features ([PMID:24185079]). Recurrent founder mutations, such as c.940+1G>A in East-Asian and African patients, underscore the variant heterogeneity.

Functional assays in Xenopus oocytes and human epithelial cells show that 10 of 11 tested SLCO2A1 mutations, including c.830del (p.Gln356AlafsTer18) and c.664G>A (p.Gly222Arg), abolish prostaglandin E2 uptake and lead to systemic PGE2 accumulation ([PMID:35877192]; [PMID:26539716]). These in vitro data confirm a loss-of-function mechanism driving PHO pathogenesis.

Phenotypic heterogeneity ranges from isolated digital clubbing to full PHO with cutis verticis gyrata, arthralgia, and, in some patients, chronic enteropathy (CEAS) caused by the same SLCO2A1 alleles. Variable expressivity necessitates molecular testing to distinguish PHO from acromegaly, inflammatory arthritis, and IBD.

Given the definitive SLCO2A1–PHO association, SLCO2A1 sequencing is recommended in suspected cases to enable accurate diagnosis, family counseling, and tailored management. Cyclooxygenase-2 inhibitors (e.g., etoricoxib) have demonstrated efficacy in lowering PGE2 levels and ameliorating clubbing, periostosis, and pachydermia, providing a targeted therapeutic option ([PMID:28425581]).

References

• American Journal of Human Genetics • 2012 • Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy. PMID:22197487
• Journal of Dermatological Science • 2012 • Identification of mutations in the prostaglandin transporter gene SLCO2A1 and its phenotype-genotype correlation in Japanese patients with pachydermoperiostosis. PMID:22906430
• Gene • 2014 • Two novel mutations in the SLCO2A1 gene in a Chinese patient with primary hypertrophic osteoarthropathy. PMID:24185079
• Journal of Bone and Mineral Research • 2017 • Clinical, Biochemical, and Genetic Features of 41 Han Chinese Families With Primary Hypertrophic Osteoarthropathy, and Their Therapeutic Response to Etoricoxib: Results From a Six-Month Prospective Clinical Intervention. PMID:28425581
• Journal of Gastroenterology and Hepatology • 2022 • Functional analysis of mutant SLCO2A1 transporters found in patients with chronic enteropathy associated with SLCO2A1. PMID:35877192
• PLoS Genetics • 2015 • A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter. PMID:26539716

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