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Background <p>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.</p> Methods <p>We describe the clinical and genetic findings of two pediatric PHO cases caused by <i>HPGD</i> variants and perform a systematic literature review of <i>HPGD</i>-related PHO cases.</p> Results <p>Both patients exhibited congenital digital clubbing and patent ductus arteriosus from birth. Radiographs&#xa0;revealed cortical bone thickening and a periosteal reaction. Patient 1 displayed gait abnormalities and delayed cranial suture closure, while&#xa0;Patient 2 had bilateral leg swelling. Whole exome sequencing identified a compound heterozygous variant (NM_000860.6: c.189C &gt; 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 &gt; 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).</p> Conclusion <p>We report the first <i>HPGD</i> c.189C &gt; 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.</p>

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

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  • 发表日期：

    2025年3月27日

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  • Jun Li,
  • Shilei Jia,
  • Jianqun Guo,
  • Wenhui Xie,
  • Yijiao Ma,
  • Xiaojie Gao,
  • Meihao Gao

摘要

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.