TNFRSF11A – Familial expansile osteolysis

Familial expansile osteolysis (FEO; MONDO:0008275) is an autosomal dominant bone dysplasia characterized by focal expansile osteolytic lesions, early-onset deafness, premature tooth loss, and generalized osteopenia (PMID:10615125). FEO arises from heterozygous tandem duplications in exon 1 of TNFRSF11A (HGNC:11908), encoding the receptor activator of NF-κB (RANK), which extend its signal peptide and drive aberrant osteoclast activation. Affected individuals present in childhood or early adulthood with progressive bone pain, deformity, and complications such as fractures and hypercalcemia.

Definitive genetic evidence includes the initial discovery of 18- and 27-base pair duplications (c.45_62dup (p.Leu16_Leu21dup), c.39_65dup (p.Leu14_Ala22dup)) across four kindreds (PMID:10615125), followed by identification of the same 18-bp duplication in two unrelated patients—one with a family history involving at least six affected relatives segregating c.45_62dup (p.Leu16_Leu21dup) (PMID:12568416). Intragenic SNP haplotyping across four pedigrees indicates at least three independent origins of the canonical 18-bp duplication (PMID:17447113).

An allelic spectrum of duplications (12–18 bp) in the signal peptide defines related RANK activation disorders including expansile skeletal hyperphosphatasia (84dup15), early-onset familial paget disease of bone (77dup27), juvenile Paget disease (87dup15), and panostotic expansile bone disease (90dup12), underscoring phenotypic overlap within the RANKL–RANK axis (PMID:25063546).

Functional assays reveal that signal peptide duplications prevent normal signal peptide cleavage, cause mutant RANK accumulation in the endoplasmic reticulum, and induce constitutive or ligand-independent NF-κB activation in vitro, confirming a gain-of-function mechanism (PMID:10615125; PMID:21472776).

A murine knock-in model of the 75dup27 insertion recapitulates human disease: heterozygous mice develop focal osteolytic lesions prevented by zoledronic acid, while homozygotes display osteopetrosis due to osteoclastogenesis failure, validating both pathogenic and dosage-dependent effects of RANK signal peptide mutations (PMID:33724536).

No studies dispute the causal role of TNFRSF11A tandem duplications in FEO. Molecular testing for exon 1 duplications guides precise diagnosis, informs autosomal dominant recurrence risk, and enables timely intervention with bisphosphonates and monitoring for skeletal complications.

In summary, autosomal dominant familial expansile osteolysis is definitively caused by heterozygous tandem duplications in TNFRSF11A that extend RANK’s signal peptide, leading to NF-κB–mediated osteoclast hyperactivity. Genetic confirmation supports targeted management and genetic counseling in affected families.

References

• Nature Genetics • 2000 • Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. PMID:10615125
• Journal of Bone and Mineral Research • 2003 • Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis. PMID:12568416
• Journal of Bone and Mineral Metabolism • 2007 • Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation. PMID:17447113
• Journal of Bone and Mineral Research • 2011 • Signal peptide mutations in RANK prevent downstream activation of NF-κB. PMID:21472776
• Bone • 2014 • Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK. PMID:25063546
• Journal of Bone and Mineral Research • 2021 • Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice. PMID:33724536

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