HPGD – Primary Hypertrophic Osteoarthropathy, Autosomal Recessive 1

Primary hypertrophic osteoarthropathy (PHO) is an autosomal recessive disorder characterized by digital clubbing, periostosis, and skin thickening. Biallelic loss-of-function variants in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, define PHOAR1.

Twelve unrelated patients (11 males, 1 female) from eleven families presented with early-onset digital clubbing (HP:0001217) and periostosis (HP:0030314) in a Chinese cohort ([PMID:35813463]). Nine were compound heterozygotes and two were homozygotes for HPGD variants; the recurrent c.310_311delCT variant was identified in eleven patients ([PMID:35813463]). An additional consanguineous case harbored a homozygous splice-site c.498+1G>A variant, expanding the allelic spectrum ([PMID:36969274]).

The variant spectrum includes six novel missense and splice-site changes (c.1A>G, c.34G>T, c.317T>A, c.475G>T, c.548C>T, c.421+1G>T) and one known frameshift (c.310_311delCT (p.Leu104fs)) ([PMID:35813463]). The hotspot c.310_311delCT allele suggests a founder effect in Chinese PHOAR1 patients.

Segregation analysis was limited to carrier testing in parents; one consanguineous pedigree confirmed recessive inheritance but no extended multiplex pedigrees have been described.

Functional assays demonstrated markedly elevated urinary prostaglandin E2 (PGE2) and reduced prostaglandin E metabolite (PGE-M) levels in affected individuals, with a significantly increased PGE2/PGE-M ratio compared to controls (P<0.001), supporting a loss-of-function mechanism ([PMID:35813463]). These findings align with deficient prostaglandin degradation observed in Hpgd−/− mouse models.

No conflicting evidence has been reported to date.

Overall, HPGD shows a Strong gene–disease association for PHOAR1 based on twelve unrelated probands with concordant biallelic variants, recurrent alleles, and consistent biochemical data. Clinical genetic testing for HPGD variants in patients with early-onset digital clubbing and periostosis is recommended to establish diagnosis and inform management.

References

• Unknown Journal | 2022 | Clinical and biochemical characteristics and HPGD gene mutations in Chinese PHOAR1 patients PMID:35813463
• Frontiers in Pediatrics | 2023 | Novel homozygous HPGD variant leads to primary hypertrophic osteoarthropathy with intussusception and acro-osteolysis in a Chinese family PMID:36969274

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