| Domain | Key facts | Evidence |
|---|---|---|
| Definition / identifier | Familial expansile osteolysis (FEO; **OMIM/MIM 174810**) is an ultrarare, progressive, Paget-like skeletal dysplasia characterized by high bone turnover, focal expansile osteolysis, early hearing loss, and permanent-tooth disease. Synonym: hereditary expansile polyostotic osteolytic dysplasia. | (pqac-00000000, pqac-00000005, pqac-00000007) |
| Causal gene / canonical variant | **TNFRSF11A** (RANK; OMIM 603499), chromosome 18q21.1–q22. Classic FEO is associated with an in-frame exon-1 **18-bp tandem duplication**, legacy notation **84dup18**, which adds six amino acids to the RANK signal peptide. Molecular discovery: Hughes et al., 2000, PMID **10615125**, [DOI](https://doi.org/10.1038/71667). Other exon-1 duplications produce overlapping RANK-associated phenotypes. | (pqac-00000000, pqac-00000011, pqac-00000015, pqac-00000026) |
| Inheritance | **Autosomal dominant**, caused by a heterozygous germline variant; multigenerational transmission and segregation are established. Penetrance was nearly complete in the Northern Ireland kindred but variable in other families; expression varies markedly even with the recurrent 18-bp duplication. De novo disease is possible, as shown for a related 12-bp RANK duplication. | (pqac-00000004, pqac-00000019, pqac-00000020, pqac-00000017) |
| Hallmark phenotypes / frequencies | In the classic Northern Ireland cohort, hearing loss occurred in approximately **95%** and external root resorption/dental abnormalities in **94%**. Hearing loss may begin by age 4 or during the first–second decade and evolve from conductive to mixed loss. Permanent-tooth resorption, mobility, fracture, and premature loss commonly follow; deciduous teeth are typically spared. | (pqac-00000001, pqac-00000004, pqac-00000025, pqac-00000028) |
| Lesions / progression | Progressive lytic lesions predominantly affect appendicular long bones—especially tibia, radius, fibula, humerus, and femur. Approximately **90%** were appendicular; expansion reached **3.5×** normal diameter. Lesions advanced **6.5–22.2 mm/year** (mean 13.3 mm/year); **12/97 lesions (12.4%)** fractured. Axial/skull disease is uncommon but documented. | (pqac-00000002, pqac-00000003, pqac-00000004, pqac-00000031) |
| Biochemical markers | Serum alkaline phosphatase and urinary hydroxyproline are commonly elevated; bone-specific ALP, osteocalcin, tartrate-resistant acid phosphatase, urinary deoxypyridinoline, and N-telopeptide may also be increased. Serum calcium, phosphate, and parathyroid hormone are usually normal before antiresorptive treatment. | (pqac-00000001, pqac-00000003, pqac-00000021) |
| Mechanism certainty | **Demonstrated:** abnormal signal-peptide cleavage, reduced surface trafficking, intracellular/ER retention of mutant RANK, impaired RANKL responsiveness, osteoclast dysregulation, and high-turnover osteolysis. **Unresolved:** constitutive gain-of-function NF-κB signaling seen in overexpression systems was not reproduced with stable single-copy expression. A proposed ER-stress/unfolded-protein-response route to ligand-independent NF-κB activation remains incompletely established. | (pqac-00000008, pqac-00000009, pqac-00000011, pqac-00000012) |
| Diagnosis | Diagnosis integrates the characteristic hearing–dental–skeletal phenotype, serum/urine turnover markers, radiographs, technetium bone scintigraphy, DXA, dental radiography/CBCT, temporal-bone CT/MRI, and confirmation of a heterozygous exon-1 **TNFRSF11A** duplication. Important differentials include ordinary Paget disease, expansile skeletal hyperphosphatasia, early-onset familial Paget disease, juvenile Paget disease, fibrous dysplasia, bone cysts, and tumors. | (pqac-00000016, pqac-00000017, pqac-00000018, pqac-00000021) |
| Treatment evidence | Evidence is limited to case reports/series and a mouse model. Alendronate **40 mg/day for 5–6 months** mineralized early lesions and improved biochemical markers/osteopenia; one case gained **2.2% lumbar-spine** and **3.0% total-hip BMD**. In 2023, zoledronic acid **0.0125 mg/kg** caused prolonged hypocalcemia (nadir **6.8 mg/dL**), while alendronate **10 mg weekly** maintained marker suppression and improved spine BMD over 22 months. Deafness generally does not respond to bisphosphonates; hearing devices/cochlear implants and multidisciplinary dental/orthopedic care are used. [Whyte et al., PMID 11889411](https://pubmed.ncbi.nlm.nih.gov/11889411/); [Craven et al., DOI](https://doi.org/10.1016/j.bone.2023.116698). | (pqac-00000016, pqac-00000017, pqac-00000018, pqac-00000021) |
| Evidence gaps | No reliable population prevalence, incidence, sex ratio, survival estimate, validated diagnostic criteria, disease-specific quality-of-life study, randomized treatment trial, approved FEO-specific therapy, prognostic model, protective variant, established environmental cause, pharmacogenomic guideline, or human single-cell/multi-omics dataset was identified. Long-term efficacy and optimal timing/dosing of antiresorptives remain unknown. | (pqac-00000001, pqac-00000016, pqac-00000023) |


*Table: Compact evidence summary of the genetic cause, hallmark manifestations, natural history, mechanism, diagnosis, treatment experience, and major knowledge gaps in familial expansile osteolysis.*