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Cranio-osteoarthropathy is a very rare autosomal-recessive condition characterized by delayed cranial suture and fontanel closure, digital clubbing, arthropathy, and periostosis. Mutations in HPGD, encoding NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase, were identified in four patients from two unrelated consanguineous families by genome-wide homozygosity mapping, with homozygous variants segregating in all affected individuals ([PMID:19568269]). The inheritance mode is autosomal recessive, and all affected individuals exhibited digital clubbing (HP:0001217) and hyperhidrosis (HP:0000975) with variable periostosis and arthropathy.
Two novel homozygous splice and frameshift mutations were reported, including c.421+1G>T in the canonical donor site, confirmed by Sanger sequencing and absent in unaffected family members ([PMID:19568269]). Clinical presentation varied between families, with inconsistent features of delayed cranial suture closure and periostosis. A separate family with autosomal-dominant isolated digital clubbing showed no HPGD mutation, indicating genetic heterogeneity for that phenotype ([PMID:19568269]).
HPGD loss-of-function is hypothesized to drive prostaglandin E₂ accumulation, but no dedicated functional assays were reported in these families. Nevertheless, known enzyme biochemistry supports haploinsufficiency as a mechanism of pathogenicity. Additional functional and animal model studies would strengthen mechanistic links but exceed current scope.
Integration of genetic and clinical data establishes a moderate level of evidence linking biallelic HPGD variants to cranio-osteoarthropathy, aiding molecular diagnosis in patients with early-onset clubbing and periostosis. Key Take-home: Testing HPGD in suspected autosomal-recessive cranio-osteoarthropathy informs diagnosis and family counseling.
Gene–Disease AssociationModerateFour probands from two unrelated families with homozygous HPGD variants and segregation by homozygosity mapping Genetic EvidenceLimitedFour probands with homozygous variants identified by genome-wide mapping; segregation consistent in two families Functional EvidenceLimitedNo targeted functional assays reported; pathogenic mechanism inferred from 15-PGDH enzymatic role |