Familial Expansile Osteolysis: Disease-Characteristics Report

Executive summary

Familial expansile osteolysis (FEO) is an ultrarare, autosomal-dominant, high-turnover skeletal dysplasia caused by heterozygous exon-1 duplications in TNFRSF11A, which encodes receptor activator of NF-κB (RANK). Its characteristic sequence is childhood hearing loss, destructive external resorption of permanent teeth, and later progressive focal osteolysis—principally of appendicular long bones—with expansion, pain, deformity, and pathological fracture. Clinical expression is highly variable, including among carriers of the recurrent 18-bp duplication. Most knowledge comes from a few extended pedigrees and case reports rather than registries or controlled trials. The most important recent clinical report, published in May 2023, suggests that early bisphosphonate treatment can suppress turnover and improve bone density, but also demonstrates a substantial risk of prolonged post-zoledronate hypocalcemia. (crone1990theradiographicfeatures pages 1-2, ralston2019rareinheritedforms pages 3-4, craven2023earlyidentificationof pages 3-4, whyte2004heritabledisordersof pages 14-14)

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

1. Disease information

Definition. FEO is a Mendelian, Paget-like disorder of osteoclast regulation characterized by generalized high bone turnover/osteopenia and progressive focal expansile osteolytic lesions. The classic phenotype includes early deafness, permanent-tooth root resorption and loss, and appendicular skeletal pain, fractures, expansion, and deformity. Advanced lesions can become thin-shelled and largely fat-filled. (whyte2004heritabledisordersof pages 1-2, whyte2004heritabledisordersofa pages 1-2)

Identifiers and terminology

• OMIM/MIM: 174810.
• Causal gene: TNFRSF11A, OMIM 603499; chromosome 18q21.1–q22.
• MONDO: a dedicated identifier could not be verified from the retrieved evidence and should be resolved directly against the current MONDO release rather than inferred.
• Orphanet, MeSH, ICD-10/ICD-11: no disease-specific identifiers were verified. In practice, coding may fall under broader osteolysis, skeletal dysplasia, or other specified bone-disease categories, but such mappings should not be treated as exact equivalents.
• Synonyms: familial expansile osteolysis; hereditary expansile polyostotic osteolytic dysplasia; FEO; “excessive RANK effect” in older literature. (whyte2004heritabledisordersof pages 1-2, whyte2004heritabledisordersofa pages 1-2)

The evidence is predominantly aggregated disease-level literature derived from individual families and patients, not population EHR data. The principal resources comprise a five-generation Northern Ireland pedigree, American, German, Spanish, and other small kindreds, and isolated cases. (crone1990theradiographicfeatures pages 1-2, whyte2004heritabledisordersof pages 2-3, whyte2004heritabledisordersof pages 14-14)

2. Etiology, risk, and protective factors

Causal factor

The primary cause is a heterozygous germline duplication within exon 1 of TNFRSF11A, altering the RANK signal peptide. Classic FEO is associated with a recurrent in-frame 18-bp duplication, conventionally reported as 84dup18, adding six amino acids. Hughes et al. identified the molecular lesion in 2000: Nature Genetics 24:45–48, PMID 10615125, DOI 10.1038/71667. (ralston2019rareinheritedforms pages 3-4, whyte2014juvenilepagetsdisease pages 14-15)

A 2023 patient with an overlapping, relatively mild RANK-duplication phenotype carried NM_003839.3:c.52_63dup, p.(Cys18_Leu21dup); both parents tested negative, supporting a de novo event. This 12-bp allele should be annotated as part of the broader allelic RANK signal-peptide disorder spectrum rather than automatically equated with classic 84dup18 FEO. (craven2023earlyidentificationof pages 3-4)

Risk factors and modifiers

• Genetic: carrying the pathogenic heterozygous duplication is the dominant risk. Family history confers a theoretical 50% transmission probability from a heterozygous affected parent.
• Expressivity/modification: severity varies markedly even for the recurrent 18-bp allele. The Spanish kindred had deafness, tooth loss, and osteoporosis but unusually few osteolytic lesions. Specific modifier genes have not been established. (whyte2004heritabledisordersof pages 14-14)
• Environmental/mechanical: trauma, fractures, surgery, and possibly pregnancy have coincided with lesion initiation or acceleration, but causality is based on observations rather than controlled evidence. Surgery appeared to accelerate extension across carpal or tarsal joints in two patients; one atypical case worsened after pregnancy and surgery. (crone1990theradiographicfeatures pages 5-6, whyte2006pagetsdiseaseof pages 6-10, marik2006familialexpansileosteolysis—not pages 3-4)
• Protective factors: no protective allele, diet, exposure, or lifestyle intervention is established. Bisphosphonates are secondary/tertiary preventive therapy, not protection from inheriting the disorder.
• Gene–environment interaction: a plausible model is that abnormal RANK-dependent remodeling renders bone unusually responsive to local mechanical injury, but this remains inferred.

No infectious cause, toxin, radiation exposure, smoking association, alcohol association, or occupational cause is supported.

3. Phenotypes

Clinical frequencies derive mainly from one family and should not be interpreted as population estimates. In another eight-person dataset, expansile lesions and early deafness each occurred in 75%, while early tooth loss occurred in 12.5%, illustrating variable expressivity. (marik2006familialexpansileosteolysis—not pages 1-3, ralston2019rareinheritedforms pages 3-4, crone1990theradiographicfeatures pages 1-2, whyte2006pagetsdiseaseof pages 4-6)

Quality of life. No FEO-specific EQ-5D, SF-36, PROMIS, or utility study was identified. Nevertheless, progressive deafness, tooth loss, pain, fractures, deformity, impaired mobility, dentures, and occasional major orthopedic procedures clearly impose substantial functional and psychosocial burdens. Severe disease has led to disability and amputation. (marik2006familialexpansileosteolysis—not pages 1-3, whyte2004heritabledisordersofa pages 2-3)

4. Genetic and molecular information

Gene: TNFRSF11A (HGNC symbol; RANK protein), encoding the receptor for RANKL and an essential regulator of osteoclast differentiation and survival.

Variant class: heterozygous, germline, in-frame tandem duplication affecting the N-terminal signal peptide. The classic allele is 84dup18 in legacy nomenclature. Available literature does not consistently provide transcript-normalized HGVS, ClinVar accession, or ACMG classification; therefore, database implementation should normalize each report against a defined current transcript before merging records. The variants are expected to be extremely rare/absent from general-population databases, but no verified gnomAD frequency was retrieved. (ralston2019rareinheritedforms pages 3-4, ralston2019rareinheritedforms pages 20-25)

Other signal-peptide duplications cause overlapping allelic disorders: 84dup15 (expansile skeletal hyperphosphatasia), 75dup27/78dup27 and related 27-bp alleles (early-onset Paget phenotypes), 87dup15 (juvenile Paget phenotype), and 90dup12 (panostotic expansile bone disease). This genotype–phenotype continuum cautions against assigning disease solely by duplication size. (ralston2019rareinheritedforms pages 20-25)

No established modifier gene, disease-specific epigenetic signature, pathogenic chromosomal rearrangement, somatic driver, or germline-repeat-expansion mechanism was identified.

5. Environmental information

FEO is not an environmentally caused or infectious disease. No reproducible toxin, pollutant, diet, exercise, smoking, or alcohol association exists. Mechanical trauma, fractures, orthopedic procedures, and orthodontic manipulation are possible local aggravators, while pregnancy-associated worsening is described in one case; all remain low-level observational evidence. Practical advice to avoid unnecessary skeletal/dental trauma is therefore precautionary rather than evidence from prevention trials. (crone1990theradiographicfeatures pages 5-6, whyte2006pagetsdiseaseof pages 6-10, marik2006familialexpansileosteolysis—not pages 3-4)

6. Mechanism and pathophysiology

Ordered causal chain

1. A heterozygous exon-1 TNFRSF11A in-frame duplication leads to elongation of the RANK signal peptide.
2. Signal-peptide alteration results in defective cleavage and impaired trafficking of mutant RANK to the plasma membrane.
3. Defective trafficking leads to intracellular, particularly ER/organized smooth-ER, retention and reduced RANKL responsiveness; these steps are experimentally supported. (alonso2021insertionmutationin pages 9-9, ralston2019rareinheritedforms pages 3-4)
4. Intracellular mutant RANK may lead to ER stress/unfolded-protein-response-mediated, ligand-independent NF-κB activity; this branch is proposed, not conclusively demonstrated. Constitutive activation seen in transient overexpression was not reproduced with stable single-copy expression. (ralston2019rareinheritedforms pages 4-6, ralston2019rareinheritedforms pages 3-4, ralston2019rareinheritedforms pages 20-25)
5. In heterozygous osteoclast-lineage cells, altered RANK signaling results in impaired RANKL-induced formation but paradoxically prolonged osteoclast survival; the latter is demonstrated in the 75dup27 mouse model, not directly for every FEO allele. (alonso2021insertionmutationin pages 1-1)
6. Osteoclast dysregulation leads to excessive focal resorption and coupled high-turnover remodeling, reflected by elevated ALP/resorption markers and avid scintigraphic uptake.
7. Persistent resorption exceeding effective replacement results in trabecular and cortical loss, marrow fibrosis/vascularity, expansion, and eventual fatty replacement.
8. Structural failure leads to pain, bowing, deformity, and pathological fractures.
9. Parallel remodeling abnormalities in the middle-ear ossicles lead to early conductive and subsequently mixed deafness, while periodontal/dental-root resorption leads to premature permanent-tooth loss. (whyte2004heritabledisordersofa pages 2-3, whyte2006pagetsdiseaseof pages 4-6)

Cells and pathways: osteoclast precursors and mature osteoclasts are primary (CL:0000778 osteoclast); osteoblasts participate in coupled remodeling (CL:0000062 osteoblast). Suggested processes include GO:0030316 osteoclast differentiation, GO:0045453 bone resorption, GO:0046849 bone remodeling, GO:0031295 T-cell-independent?—not recommended here—and GO:0034976 response to endoplasmic-reticulum stress. Relevant signaling includes RANKL–RANK–TRAF6–NF-κB and downstream osteoclastogenesis.

Histology includes abundant osteoclasts and osteoblasts, giant bizarre multinucleated osteoclasts, woven trabeculae, fibrous/vascular marrow, scant matrix, and late fatty replacement. Unlike ordinary Paget disease, a mosaic pattern is uncommon. Historical “viral-like inclusions” in osteoclast nuclei are not evidence of an infectious etiology. (whyte2004heritabledisordersof pages 1-2, crone1990theradiographicfeatures pages 2-5, crone1990theradiographicfeatures pages 5-6)

No FEO-specific human transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or integrated multi-omics dataset was identified.

7. Anatomical structures affected

The principal system is the skeleton/connective tissue. Approximately 90% of classic lesions were appendicular. Common sites are tibia, radius, fibula, humerus, and femur; lower-limb and distal-to-knee involvement is prominent. Suggested terms include UBERON:0000979 hindlimb, UBERON:0000978 forelimb, and the corresponding individual long-bone terms. (ralston2019rareinheritedforms pages 3-4, crone1990theradiographicfeatures pages 2-5)

Secondary sites include permanent teeth/roots, periodontal structures, temporal bone, and auditory ossicles—especially the incus. Pelvis, spine, skull, ribs, mandible, and girdles are less often affected but cannot be considered universally spared. Right-sided lesions were more frequent in one series (60 right versus 37 left), but bilateral tibial disease became common with age. (crone1990theradiographicfeatures pages 2-5, crone1990theradiographicfeatures pages 5-6)

At tissue level, cortical and trabecular bone and marrow are affected. At subcellular level, the RANK secretory pathway implicates the ER, Golgi, plasma membrane, and NF-κB signaling machinery.

8. Temporal development

The usual sequence is insidious childhood hearing impairment, adolescent permanent-tooth disease, and focal skeletal disease from adolescence or adulthood. Bone pain began at 18–44 years and focal radiographic disease at 15–45 years in the classic cohort. Lesions progressed linearly at 6.5–22.2 mm/year, mean 13.3 mm/year, through lytic, expansile, and deforming/mechanical-failure phases. (crone1990theradiographicfeatures pages 2-5, crone1990theradiographicfeatures pages 1-2)

The course is chronic and lifelong, but site-specific activity can become “burnt out.” Childhood onset is documented: one patient fractured at 5, had relative quiescence from 9 to pregnancy at 20, and later accelerated disease. Scintigraphy may become abnormal before radiographs, defining a potential window for monitoring and antiresorptive intervention. No reliable spontaneous-remission rate exists. (crone1990theradiographicfeatures pages 2-5, marik2006familialexpansileosteolysis—not pages 3-4)

9. Inheritance and population

Inheritance is autosomal dominant with variable expressivity and probably age-dependent penetrance. The Northern Ireland kindred showed near-complete penetrance: 40 of 90 examined family members were affected, while 51 children of unaffected parents had no signs. Published estimates include 46 affected individuals over five generations in that kindred and 20 affected individuals across four generations in the Spanish family. (crone1990theradiographicfeatures pages 1-2, whyte2004heritabledisordersof pages 2-3, whyte2004heritabledisordersof pages 14-14)

FEO has been reported in Northern Irish, German, American, Spanish, Czech, Australian, and other patients, but the literature remains too sparse for prevalence, incidence, carrier-frequency, sex-ratio, ethnic-risk, or geographic-rate estimates. A 2006 report stated that only three kinships and two unrelated American individuals had been recognized worldwide at that time. No convincing anticipation, founder effect, consanguinity effect, or germline mosaicism rate is established. De novo mutation is biologically and clinically possible. (marik2006familialexpansileosteolysis—not pages 1-3, craven2023earlyidentificationof pages 3-4)

10. Diagnostics

Recommended approach

1. Recognize the combination of early hearing loss, permanent-tooth external root resorption, elevated turnover, and appendicular expansile osteolysis.
2. Measure serum total/bone-specific ALP, calcium, phosphate, creatinine, PTH, and 25-hydroxyvitamin D; consider osteocalcin and serum/urine resorption markers.
3. Obtain targeted radiographs and whole-body technetium bone scintigraphy; use DXA to quantify generalized low bone mass.
4. Perform panoramic dental imaging or CBCT and formal audiology; temporal-bone CT/MRI may define ossicular/inner-ear pathology.
5. Confirm a heterozygous exon-1 TNFRSF11A duplication by sequencing with duplication-sensitive analysis and parental/segregation testing. (craven2023earlyidentificationof pages 3-4, craven2023earlyidentificationof pages 1-3)

Single-gene sequencing or a high-turnover bone-dysplasia/Paget panel is efficient when the phenotype is typical. Exome or genome sequencing is appropriate for atypical or panel-negative disease, provided the pipeline detects small tandem duplications. CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing are not first-line tests for classic FEO. No validated RNA, proteomic, metabolomic, epigenomic, or liquid-biopsy diagnostic exists.

Differential diagnosis: ordinary Paget disease; early-onset familial Paget disease; expansile skeletal hyperphosphatasia; juvenile Paget disease due to TNFRSF11B; panostotic expansile bone disease; fibrous dysplasia; primary bone cysts/tumors; giant-cell lesions; and other hereditary osteolysis syndromes. FEO favors early deafness/root resorption, appendicular advancing lysis without the later dominant sclerotic phase of ordinary Paget disease, and a signal-peptide TNFRSF11A duplication. (whyte2006pagetsdiseaseof pages 6-10, craven2023earlyidentificationof pages 3-4, whyte2002familialexpansileosteolysis pages 13-15)

No consensus society diagnostic criteria or population/newborn-screening program exists. Cascade molecular testing is appropriate for at-risk relatives.

11. Outcome and prognosis

No survival curve, disease-specific mortality rate, or life-expectancy estimate is available. Morbidity is driven by progressive deafness, tooth loss, pain, deformity, osteoporosis, and fracture. Fractures generally heal, but advanced lesions may be refractory to antiresorptives and can cause profound disability. (crone1990theradiographicfeatures pages 2-5, whyte2006pagetsdiseaseof pages 6-10)

Osteosarcoma has been reported in association with FEO, including metastatic osteosarcoma in one family and a 17-year-old case, but the absolute risk is unknown and causal enrichment cannot be inferred from isolated reports. Any new persistent pain, enlarging mass, or destructive radiographic change warrants urgent oncologic assessment. (whyte2006pagetsdiseaseof pages 4-6)

Probable adverse prognostic features are early skeletal onset, rapid lesion extension, multifocal disease, fracture/deformity, very high turnover, and late fat-filled lesions. These have not been validated in a prognostic model.

12. Treatment and real-world implementation

There is no approved disease-specific or curative therapy and no randomized FEO trial. Management is multidisciplinary.

Antiresorptives

Bisphosphonates are the best-supported pharmacotherapy (NCIT: Bisphosphonate; Alendronate; Pamidronate; Zoledronic Acid). Historical calcitonin reduced symptoms without clear radiographic benefit; dichloromethylene diphosphonate was ineffective, and pamidronate produced variable benefit. Oral alendronate 40 mg/day for 5–6 months was associated with early-lesion mineralization, biochemical normalization, and improved osteopenia; one patient gained 2.2% lumbar-spine and 3.0% total-hip BMD, with effects persisting up to two years in some observations. Established deafness did not improve. (whyte2006pagetsdiseaseof pages 6-10, whyte2002familialexpansileosteolysis pages 13-15)

The leading recent report—Craven et al., Bone, published May 2023, DOI 10.1016/j.bone.2023.116698—described a 10-year-old girl with a de novo 12-bp RANK duplication. Zoledronic acid 0.0125 mg/kg caused prolonged asymptomatic hypocalcemia, nadir 6.8 mg/dL at 2.5 days despite calcium 700 mg three times daily and calcitriol 0.5 μg twice daily. Subsequent alendronate 10 mg weekly maintained marker suppression and improved spinal BMD over 22 months; no pain, fracture, deformity, or focal lesion developed, although dental resorption persisted. This supports early intervention but remains one case with an overlapping allelic phenotype, not proof of FEO disease modification. (craven2023earlyidentificationof pages 6-8, craven2023earlyidentificationof pages 3-4)

Before potent antiresorptives, correct vitamin-D/calcium deficiency, assess renal function, and plan intensive calcium monitoring. The hypocalcemia resembles a high-turnover “hungry-bone” response.

Hearing, dental, orthopedic, and supportive care

Hearing aids, ossicular surgery in selected conductive disease, and cochlear implantation are used. Bilateral cochlear implantation at 34 months was successful in the 2023 patient. Dental care should emphasize surveillance of permanent-root resorption, preservation where feasible, prosthodontics, and caution with orthodontic force or invasive surgery. Orthopedic management includes fracture care, stabilization/correction of deformity, mobility support, analgesia, and physical/occupational therapy. (craven2023earlyidentificationof pages 3-4, whyte2002familialexpansileosteolysis pages 13-15)

Denosumab, RANK/RANKL-targeted drugs, gene therapy, cell therapy, CRISPR, and RNA therapy are not established for FEO. Intracellular retention of mutant RANK raises a theoretical concern that extracellular RANKL blockade may not correct all abnormal signaling. No FEO-specific NCT study was found. (whyte2014juvenilepagetsdisease pages 11-14, ralston2019rareinheritedforms pages 1-3)

13. Prevention

Primary prevention by lifestyle or immunization is not applicable. Reproductive options following molecular diagnosis include genetic counseling, prenatal diagnosis, and preimplantation genetic testing; these prevent transmission or enable informed reproductive decisions but do not alter an affected embryo’s biology.

Secondary prevention comprises cascade testing, childhood audiology and dental surveillance, turnover-marker measurement, scintigraphy/radiography when indicated, and early specialist assessment before irreversible skeletal damage. Tertiary prevention includes antiresorptive control of turnover, calcium/vitamin-D optimization, fall and trauma reduction, prompt fracture treatment, hearing rehabilitation, dental preservation, and deformity management. Trauma/orthodontic precautions are reasonable but supported only by observational evidence. (crone1990theradiographicfeatures pages 5-6, whyte2006pagetsdiseaseof pages 6-10, craven2023earlyidentificationof pages 1-3)

14. Other species and natural disease

No naturally occurring veterinary syndrome convincingly established as the direct orthologue of human FEO was identified. Accordingly, no breed association, VBO term, zoonotic potential, or cross-species transmission applies. TNFRSF11A is evolutionarily conserved; the relevant experimental orthologue is murine Tnfrsf11a. FEO is genetic and noncommunicable.

15. Model organisms

The most informative model is a genetically engineered mouse carrying the human-disease-related Tnfrsf11a 75dup27 insertion. Heterozygous mice developed age-dependent, Paget-like focal hind-limb osteolytic lesions by approximately 12 months. Their marrow showed impaired RANKL-induced osteoclast formation/signaling but increased osteoclast survival independent of RANKL. Zoledronic acid completely prevented lesion development. Homozygous mice instead had congenital osteopetrosis, metaphyseal widening, sclerosis, retained mineralized cartilage, absent osteoclasts, and failure of marrow cells to form osteoclasts after RANKL plus M-CSF. Alonso et al., March 2021, DOI 10.1002/jbmr.4288. (alonso2021insertionmutationin pages 9-9, alonso2021insertionmutationin pages 1-1)

This model recapitulates age-dependent focal osteolysis and demonstrates a preventive antiresorptive effect, but it models a 27-bp early-onset Paget allele rather than classic FEO 84dup18. Its paradoxical homozygous osteopetrosis also shows that simple “constitutive RANK gain of function” is inadequate as a universal mechanistic explanation.

Evidence appraisal and research gaps

The foundational evidence is human clinical and pedigree-based, including the molecular discovery (PMID 10615125), five-generation American characterization (PMID 11889411), allelic expansile skeletal hyperphosphatasia study (PMID 11771666), Spanish family study (PMID 12362049), two unrelated FEO cases (PMID 12568416), dental report (PMID 10509339), and incus-necrosis report (PMID 8643278). (whyte2014juvenilepagetsdisease pages 14-15, whyte2014juvenilepagetsdisease pages 15-16)

A representative primary-paper abstract describes FEO as a “rare autosomal dominant disorder characterized by striking focal expansile osteolytic bone lesions and generalized osteopenia,” often with early hearing loss and dental disease. That wording accurately summarizes the phenotype but should not obscure substantial interfamily variability. The major expert conclusion from recent mechanistic work is that defective RANK processing and osteoclast dysregulation are established, whereas the precise route from intracellular mutant receptor to focal hyperresorption remains unresolved. (ralston2019rareinheritedforms pages 4-6, ralston2019rareinheritedforms pages 3-4, craven2023earlyidentificationof pages 6-8)

Critical gaps include reliable prevalence and natural-history registries, standardized phenotype/variant curation, prospective pediatric surveillance, disease-specific quality-of-life measurement, direct studies of classic 84dup18 osteoclasts, biomarkers predicting lesion onset, and controlled comparisons of oral versus intravenous antiresorptive regimens. No substantial FEO-specific 2024 clinical or omics study was identified; the May 2023 report remains the most directly relevant recent clinical development.

References

1. (crone1990theradiographicfeatures pages 1-2): MalcolmD. Crone and RichardG.H. Wallace. The radiographic features of familial expansile osteolysis. Skeletal Radiology, 19:245-250, May 1990. URL: https://doi.org/10.1007/bf00191665, doi:10.1007/bf00191665. This article has 43 citations and is from a peer-reviewed journal.

2. (ralston2019rareinheritedforms pages 3-4): Stuart H. Ralston and J. Paul Taylor. Rare inherited forms of paget’s disease and related syndromes. Calcified Tissue International, 104:501-516, Feb 2019. URL: https://doi.org/10.1007/s00223-019-00520-5, doi:10.1007/s00223-019-00520-5. This article has 40 citations and is from a peer-reviewed journal.

3. (craven2023earlyidentificationof pages 3-4): Meghan Craven, Mary Ellen Vajravelu, Karuna V. Shekdar, Michael A. Levine, Steven Mumm, Michael P. Whyte, and Edna E. Mancilla. Early identification of a 12-bp tandem duplication in tnfrsf11a encoding receptor activator of nuclear factor-kappa b (rank): clinical characterization and response to bisphosphonate therapy. Bone, 170:116698, May 2023. URL: https://doi.org/10.1016/j.bone.2023.116698, doi:10.1016/j.bone.2023.116698. This article has 5 citations and is from a domain leading peer-reviewed journal.

4. (whyte2004heritabledisordersof pages 14-14): MP Whyte and S Mumm. Heritable disorders of the rankl/opg/rank signaling pathway. Unknown journal, 2004.

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7. (ralston2019rareinheritedforms pages 1-3): Stuart H. Ralston and J. Paul Taylor. Rare inherited forms of paget’s disease and related syndromes. Calcified Tissue International, 104:501-516, Feb 2019. URL: https://doi.org/10.1007/s00223-019-00520-5, doi:10.1007/s00223-019-00520-5. This article has 40 citations and is from a peer-reviewed journal.

8. (whyte2014juvenilepagetsdisease pages 14-15): Michael P. Whyte, Cristina Tau, William H. McAlister, Xiafang Zhang, Deborah V. Novack, Virginia Preliasco, Eduardo Santini-Araujo, and Steven Mumm. Juvenile paget's disease with heterozygous duplication within tnfrsf11a encoding rank. Bone, 68:153-61, Nov 2014. URL: https://doi.org/10.1016/j.bone.2014.07.019, doi:10.1016/j.bone.2014.07.019. This article has 63 citations and is from a domain leading peer-reviewed journal.

9. (whyte2004heritabledisordersof pages 2-3): MP Whyte and S Mumm. Heritable disorders of the rankl/opg/rank signaling pathway. Unknown journal, 2004.

10. (marik2006familialexpansileosteolysis—not pages 1-3): I. Marik, A. Maříková, E. Hyánková, and K. Kozłowski. Familial expansile osteolysis—not exclusively an adult disorder. Skeletal Radiology, 35:872-875, Feb 2006. URL: https://doi.org/10.1007/s00256-005-0077-x, doi:10.1007/s00256-005-0077-x. This article has 19 citations and is from a peer-reviewed journal.

11. (whyte2004heritabledisordersofa pages 2-3): MP Whyte and S Mumm. Heritable disorders of the rankl/opg/rank signaling pathway. Unknown journal, 2004.

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13. (crone1990theradiographicfeatures pages 2-5): MalcolmD. Crone and RichardG.H. Wallace. The radiographic features of familial expansile osteolysis. Skeletal Radiology, 19:245-250, May 1990. URL: https://doi.org/10.1007/bf00191665, doi:10.1007/bf00191665. This article has 43 citations and is from a peer-reviewed journal.

14. (marik2006familialexpansileosteolysis—not pages 3-4): I. Marik, A. Maříková, E. Hyánková, and K. Kozłowski. Familial expansile osteolysis—not exclusively an adult disorder. Skeletal Radiology, 35:872-875, Feb 2006. URL: https://doi.org/10.1007/s00256-005-0077-x, doi:10.1007/s00256-005-0077-x. This article has 19 citations and is from a peer-reviewed journal.

15. (craven2023earlyidentificationof pages 1-3): Meghan Craven, Mary Ellen Vajravelu, Karuna V. Shekdar, Michael A. Levine, Steven Mumm, Michael P. Whyte, and Edna E. Mancilla. Early identification of a 12-bp tandem duplication in tnfrsf11a encoding receptor activator of nuclear factor-kappa b (rank): clinical characterization and response to bisphosphonate therapy. Bone, 170:116698, May 2023. URL: https://doi.org/10.1016/j.bone.2023.116698, doi:10.1016/j.bone.2023.116698. This article has 5 citations and is from a domain leading peer-reviewed journal.

16. (alonso2021insertionmutationin pages 9-9): Nerea Alonso, Sachin Wani, Lorraine Rose, Rob J. van't Hof, Stuart H. Ralston, and Omar M.E. Albagha. Insertion mutation in tnfrsf11a causes a paget's disease–like phenotype in heterozygous mice and osteopetrosis in homozygous mice. Journal of Bone and Mineral Research, 36:1376-1386, Mar 2021. URL: https://doi.org/10.1002/jbmr.4288, doi:10.1002/jbmr.4288. This article has 15 citations and is from a highest quality peer-reviewed journal.

17. (ralston2019rareinheritedforms pages 4-6): Stuart H. Ralston and J. Paul Taylor. Rare inherited forms of paget’s disease and related syndromes. Calcified Tissue International, 104:501-516, Feb 2019. URL: https://doi.org/10.1007/s00223-019-00520-5, doi:10.1007/s00223-019-00520-5. This article has 40 citations and is from a peer-reviewed journal.

18. (ralston2019rareinheritedforms pages 20-25): Stuart H. Ralston and J. Paul Taylor. Rare inherited forms of paget’s disease and related syndromes. Calcified Tissue International, 104:501-516, Feb 2019. URL: https://doi.org/10.1007/s00223-019-00520-5, doi:10.1007/s00223-019-00520-5. This article has 40 citations and is from a peer-reviewed journal.

19. (whyte2006pagetsdiseaseof pages 6-10): MICHAEL P. WHYTE. Paget's disease of bone and genetic disorders of rankl/opg/rank/nf‐κb signaling. Annals of the New York Academy of Sciences, 1068:143-164, Apr 2006. URL: https://doi.org/10.1196/annals.1346.016, doi:10.1196/annals.1346.016. This article has 128 citations and is from a peer-reviewed journal.

20. (whyte2002familialexpansileosteolysis pages 13-15): MICHAEL P. WHYTE, WILLIAM R. REINUS, MICHELLE N. PODGORNIK, and BARBARA G. MILLS. Familial expansile osteolysis (excessive rank effect) in a 5-generation american kindred. Medicine, 81:101-121, Mar 2002. URL: https://doi.org/10.1097/00005792-200203000-00002, doi:10.1097/00005792-200203000-00002. This article has 54 citations and is from a peer-reviewed journal.

21. (crone1990theradiographicfeatures pages 5-6): MalcolmD. Crone and RichardG.H. Wallace. The radiographic features of familial expansile osteolysis. Skeletal Radiology, 19:245-250, May 1990. URL: https://doi.org/10.1007/bf00191665, doi:10.1007/bf00191665. This article has 43 citations and is from a peer-reviewed journal.

22. (alonso2021insertionmutationin pages 1-1): Nerea Alonso, Sachin Wani, Lorraine Rose, Rob J. van't Hof, Stuart H. Ralston, and Omar M.E. Albagha. Insertion mutation in tnfrsf11a causes a paget's disease–like phenotype in heterozygous mice and osteopetrosis in homozygous mice. Journal of Bone and Mineral Research, 36:1376-1386, Mar 2021. URL: https://doi.org/10.1002/jbmr.4288, doi:10.1002/jbmr.4288. This article has 15 citations and is from a highest quality peer-reviewed journal.

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24. (whyte2014juvenilepagetsdisease pages 11-14): Michael P. Whyte, Cristina Tau, William H. McAlister, Xiafang Zhang, Deborah V. Novack, Virginia Preliasco, Eduardo Santini-Araujo, and Steven Mumm. Juvenile paget's disease with heterozygous duplication within tnfrsf11a encoding rank. Bone, 68:153-61, Nov 2014. URL: https://doi.org/10.1016/j.bone.2014.07.019, doi:10.1016/j.bone.2014.07.019. This article has 63 citations and is from a domain leading peer-reviewed journal.

25. (whyte2014juvenilepagetsdisease pages 15-16): Michael P. Whyte, Cristina Tau, William H. McAlister, Xiafang Zhang, Deborah V. Novack, Virginia Preliasco, Eduardo Santini-Araujo, and Steven Mumm. Juvenile paget's disease with heterozygous duplication within tnfrsf11a encoding rank. Bone, 68:153-61, Nov 2014. URL: https://doi.org/10.1016/j.bone.2014.07.019, doi:10.1016/j.bone.2014.07.019. This article has 63 citations and is from a domain leading peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

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Unresolved references

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• DOI:10.1016/j.bone.2023.116698)—described (1 mention) - Identifier did not resolve to a record

Term Validation

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Every term resolved, and every label the report gave matched.