Juvenile Paget’s disease in two Chinese pedigrees carrying distinct novel homozygous TNFRSF11B variants: clinical manifestations, management, and follow-up
Authors' conclusion
This study expanded the genotypic and phenotypic spectrum of OPG-deficient JPD and confirmed that both zoledronic acid and denosumab were effective treatments, although response and safety differed according to age and baseline disease activity, supporting individualized antiresorptive management.
Study context
- Population
- Patients with a clinical diagnosis of juvenile Paget's disease (JPD) carrying homozygous TNFRSF11B variants, from two unrelated Chinese pedigrees
- Participants
- 2 patients
- Exposure
- Patient 1 vs Patient 2
- Outcome
- Genetic findings
Methodological detailscase report, familial segregation, AlphaFold-based structural analysis
- Case report
- Familial segregation
- AlphaFold-based structural analysis
Main finding
As reported in the abstract
- Two novel homozygous TNFRSF11B missense variants: c.544 G > T (p. Asp182Tyr) in P1 and c.307 C > T (p. Arg103Cys) in P2; both families showed heterozygous parental carrier status
- Both variants classified as variants of uncertain significance (VUS)
Observational data: associations, not effects.
Further findings
Alkaline phosphatase (ALP) with zoledronic acid in P1 · 6 weeks
- ALP reduced from 5069 to 1917 U/L
- 5069 to 1917 U/L
- Improved skeletal mineralization
Lumbar spine bone mineral density (BMD) with denosumab in P2 · 6 months
- Increase in lumbar spine BMD
- 17.5%
- Markedly suppressed bone turnover markers, reduced pain, improved mobility, prevented new fractures during the 1-year follow-up
Clinical phenotype
- P1: severe early-onset disease with recurrent fractures, macrocephaly, long-bone bowing, markedly elevated bone turnover markers, diffuse skeletal involvement
- P2: milder but progressive deforming phenotype with scoliosis, profound hearing loss, low lumbar spine BMD, persistent biochemical hyperturnover, extensive polyostotic skeletal disease
Original publication
Juvenile Paget’s disease in two Chinese pedigrees carrying distinct novel homozygous TNFRSF11B variants: clinical manifestations, management, and follow-up. Osteoporos Int. Published 12 November 2026. doi:10.
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