Two cases of primary hypertrophic osteoarthropathy caused by HPGD variants: a case report and literature review.

Abstract

Background: Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder primarily characterized by digital clubbing, pachydermia, and periostitis. The rarity of this disease often leads to misdiagnosis or delayed diagnosis.

Methods: We describe the clinical and genetic findings of two pediatric PHO cases caused by HPGD variants and perform a systematic literature review of HPGD-related PHO cases.

Results: Both patients exhibited congenital digital clubbing and patent ductus arteriosus from birth. Radiographs revealed cortical bone thickening and a periosteal reaction. Patient 1 displayed gait abnormalities and delayed cranial suture closure, while Patient 2 had bilateral leg swelling. Whole exome sequencing identified a compound heterozygous variant (NM_000860.6: c.189C > A, p.C63* and NM_000860.6: c.310_311delCT, p. L104Afs*3) in Patient 1 and a homozygous splice-site variant (NG_011689.1(NM_000860.6): c.324 + 5G > A) in Patient 2. All variants were classified as pathogenic based on the American College of Medical Genetics and Genomics criteria. Among 89 reviewed cases, the c.310_311delCT variant accounted for 37.1% (33/89), predominantly in homozygous form (60.6%, 20/33). The median urinary prostaglandin E2 (PGE2)-to-creatinine ratio in PHO patients was 627.1 ng/mmol (normal: 61.49 ng/mmol). Notably, the median age of symptom onset was 5.1 years, while diagnosis occurred at 22.1 years, with a male predominance (male-to-female ratio: 2.2:1).

Conclusion: We report the first HPGD c.189C > A variant, expanding the genetic spectrum of PHO. The c.310_311delCT variant represents a recurrent hotspot, predominantly in homozygosity. Our findings highlight the importance of early genetic testing and multidisciplinary management to reduce diagnostic delays and improve outcomes.