TNFRSF11B – Juvenile Paget Disease

Juvenile Paget disease (JPD) is an ultra-rare autosomal recessive osteopathy characterized by accelerated bone turnover, deformities of long bones, kyphosis, protrusio acetabuli and osteopenia. Initial linkage in Navajo families mapped to chromosome 8q24.2 implicating TNFRSF11B, which encodes osteoprotegerin (OPG), a critical decoy receptor for RANK-ligand (PMID:12124406). Affected individuals present in infancy or early childhood with fractures, deformity, deafness and hyperphosphatasemia, progressing variably depending on mutation severity.

Genetic evidence includes homozygous in-frame and truncating TNFRSF11B mutations in multiple unrelated pedigrees. Over 20 probands from >9 families have been reported, with biallelic segregation consistent with autosomal recessive inheritance (PMID:14672344, PMID:12189164). Variants include missense changes (e.g., c.130T>C (p.Cys44Arg)), in-frame deletions (c.544_546del (p.Asp182del)), frameshift duplications (c.25_28dup (p.Val10fs)), and large gene deletions, establishing a diverse allelic spectrum.

Functional studies demonstrate loss-of-function as the disease mechanism. The p.Asp182del mutant is poorly secreted and binds RANKL inefficiently, leading to unchecked osteoclastogenesis (PMID:16491292). Truncation at p.Gln325Ter abolishes OPG homodimerization and ligand binding, confirmed by Western blot and ELISA (PMID:15777670). Recombinant OPG therapy in adult siblings suppresses bone resorption, increases bone mass and improves radiographic features without major adverse events (PMID:16135836).

No credible reports dispute the TNFRSF11B–JPD association. Genotype–phenotype correlations demonstrate that cysteine-rich domain disruptions yield severe early-onset disease, whereas C-terminal variants confer milder, intermediate phenotypes. Therapeutic interventions with bisphosphonates and recombinant OPG have shown efficacy in reducing bone turnover and deformity progression.

In summary, biallelic TNFRSF11B variants cause definitive juvenile Paget disease by osteoprotegerin deficiency leading to accelerated osteoclast activity. Genetic testing of TNFRSF11B is recommended for diagnosis, prognostic stratification and guiding treatment, with OPG pathway modulation offering clinical benefit.

References

• The New England journal of medicine • 2002 • Osteoprotegerin deficiency and juvenile Paget's disease. PMID:12124406
• Journal of bone and mineral research • 2003 • Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype. PMID:14672344
• Human Molecular Genetics • 2002 • A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. PMID:12189164
• Bone • 2005 • An intermediate form of juvenile Paget's disease caused by a truncating TNFRSF11B mutation. PMID:15777670
• The New England journal of medicine • 2005 • Recombinant osteoprotegerin for juvenile Paget's disease. PMID:16135836
• Journal of bone and mineral research • 2006 • Deletion of aspartate 182 in OPG causes juvenile Paget's disease by impairing both protein secretion and binding to RANKL. PMID:16491292

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