Juvenile Paget’s disease in two Chinese pedigrees carrying distinct novel homozygous TNFRSF11B variants: clinical manifestations, management, and follow-up

Juvenile Paget's disease (JPD) is an ultra-rare autosomal recessive skeletal disorder caused by loss-of-function mutations in TNFRSF11B, which encodes osteoprotegerin (OPG), resulting in enhanced osteoclastic bone resorption. PURPOSE: To describe the clinical, genetic, and therapeutic features of two patients with a clinical diagnosis of JPD who carried distinct homozygous TNFRSF11B variants. METHODS: Clinical and longitudinal follow-up analyses of two unrelated Chinese pedigrees with JPD were performed. Clinical assessment, biochemical testing, skeletal imaging, Sanger sequencing of TNFRSF11B with familial segregation, in silico pathogenicity prediction, and AlphaFold-based structural analysis were undertaken. RESULTS: Patient 1 (P1), a 3-year-old boy, had severe early-onset disease with recurrent fractures, macrocephaly, long-bone bowing, markedly elevated bone turnover markers, and diffuse skeletal involvement on imaging. Patient 2 (P2), a 35-year-old woman, had a milder but progressive deforming phenotype with scoliosis, profound hearing loss, low lumbar spine bone mineral density (BMD), persistent biochemical hyperturnover, and extensive polyostotic skeletal disease on imaging. Sanger sequencing identified 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 were classified as variants of uncertain significance (VUS) by the genetic testing laboratory. Zoledronic acid in P1 rapidly reduced alkaline phosphatase (ALP) from 5069 to 1917 U/L at 6 weeks and improved skeletal mineralization, but was complicated by hungry bone syndrome. Denosumab in P2 markedly suppressed bone turnover markers, reduced pain, improved mobility, prevented new fractures during the 1-year follow-up, and increased lumbar spine BMD by 17.5% at 6 months. 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.