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Primary hypertrophic osteoarthropathy (PHO; MONDO:0016620) is an autosomal recessive disorder characterized by digital clubbing, periostosis, pachydermia, hyperhidrosis and arthralgia. HPGD (HGNC:5154) encodes the NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase, the key enzyme in prostaglandin E2 (PGE2) catabolism. Biallelic loss-of-function variants in HPGD lead to elevated PGE2, driving the PHO phenotype. Over the past decade, multiple independent reports across diverse populations have delineated the clinical and molecular spectrum of HPGD-related PHO, establishing a robust gene–disease relationship to guide diagnosis and management.
Inheritance of HPGD-related PHO is autosomal recessive, with patients harboring homozygous or compound heterozygous variants. A 13-year-old boy with mild PHO was found to carry a homozygous splice-donor variant c.217+1G>A, leading to exon 2 skipping and reduced enzyme activity (PMID:20406614). Two Turkish siblings exhibited a homozygous frameshift c.310_311del (p.Leu104fs) and responded to sulfasalazine and methotrexate therapy (PMID:24533558). A recurrent c.38C>A (p.Ala13Glu) variant was identified homozygously in two unrelated adults, enabling reclassification to likely pathogenic based on homozygosity in multiple probands and absence from population databases (PMID:37591693).
Segregation analysis across at least 19 affected relatives in 11 families confirms co-segregation of biallelic HPGD variants with the PHO phenotype (PMID:19568269; PMID:20299379). To date, over 89 patients have been reported, harboring more than 25 distinct HPGD variants: ≥10 splice-site changes (e.g., c.217+1G>A), ≥12 truncating/frameshift alleles (e.g., p.Leu59ValfsTer8), and ≥4 missense substitutions (e.g., p.Arg163His) (PMID:40140750). The c.310_311del founder allele recurs in European and Asian cohorts, supporting targeted screening.
Functional studies demonstrate that HPGD loss-of-function leads to markedly elevated PGE2 and reduced PGE-M levels in serum and urine, correlating with clinical severity (PMID:21426412). Patient-derived assays show absent or diminished 15-PGDH activity, consistent with haploinsufficiency. COX-2 inhibitor treatment (e.g., celecoxib, etoricoxib) reduces PGE2 levels and alleviates symptoms, providing in vivo functional concordance and therapeutic proof-of-principle (PMID:39840454).
Although SLCO2A1 variants also underlie PHO via disrupted PGE2 transport, numerous cohorts lacking SLCO2A1 mutations underscore HPGD as the primary gene in many cases (PMID:22906430). No studies have refuted the HPGD–PHO association, and reports of alternative phenotypes are absent, minimizing conflicting evidence.
Collectively, genetic, segregation, and experimental data support a ClinGen gene–disease validity classification of Strong. HPGD testing should be prioritized in patients presenting early-onset digital clubbing, periostosis, and pachydermia. Early molecular diagnosis informs genetic counseling and enables targeted COX-2 inhibitor therapy. Key take-home: Biallelic HPGD loss-of-function variants reliably predict PHO and guide precision management.
Gene–Disease AssociationStrongOver 89 probands from >50 families, consistent biallelic HPGD mutations segregating with phenotype, and concordant functional data [PMID:20406614] Genetic EvidenceStrongOver 25 distinct HPGD variants including ≥10 splice-site, ≥12 truncating, and ≥4 missense across 89 patients; evidence reaches genetic evidence cap Functional EvidenceModerateFunctional studies show loss-of-function enzyme activity leading to PGE2 accumulation in patient cells and improvement with COX-2 inhibitors |