🏷

Classifications

Harrison's Part

ISDS Skeletal Nosology

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Transmitted as an autosomal dominant trait through five generations of the original Northern Irish kindred and in every family reported since. The heterozygous duplication is highly penetrant, but expression varies markedly between and within families carrying the identical allele: some relatives have deafness and tooth loss with few or no osteolytic lesions, others have extensive limb and even skull disease from childhood. Sporadic cases with no family history occur. Penetrance is recorded as complete on the strength of the kindred descriptions; no formal penetrance estimate has been published.

Autosomal dominant inheritance Penetrance: COMPLETE Expressivity: VARIABLE

Show evidence (4 references)

PMID:3346299 SUPPORT Human Clinical

"We report 40 cases in one family of an autosomal dominant bone dysplasia, which, though similar in some aspects to Paget's disease, seems unique in some features and in its natural history."

The original description of the Northern Irish kindred establishes the autosomal dominant pattern from 40 affected members of one family.

PMID:7911698 SUPPORT Human Clinical

"Familial expansile osteolysis is a rare bone dysplasia which is transmitted as an autosomal dominant trait in a large kindred in Northern Ireland."

The linkage study restates the dominant transmission on which the 18q mapping depended.

PMID:17447113 SUPPORT Human Clinical

"Despite having the identical mutation, phenotypic variations among affected individuals of the same and different pedigrees were noted."

Supports variable expressivity: the same 18-bp duplication produces different phenotypes within and between pedigrees.

+ 1 more reference

?

Discussions and Knowledge Gaps

3

Does the heterozygous TNFRSF11A signal-peptide duplication cause osteoclast overactivity through constitutive, ligand-independent NF-kappaB signalling by the mutant receptor, or through an effect of the misprocessed, ER-retained protein on the wild-type receptor or on the cell, such as an unfolded-protein response?

KNOWLEDGE GAP OPEN feo_constitutive_activation_versus_misprocessing

Attached to

pathophysiology#Failure of RANK Signal-Peptide Cleavage and Endoplasmic Reticulum Retention pathophysiology#Ligand-Independent RANK Signalling and NF-kappaB Activation

The two positions are both in the literature and are not reconciled. The discovery study found increased NF-kappaB signalling from recombinant mutant RANK and called the mutations activating, and reviews still state the mechanism as ligand-independent NF-kappaB activation. The 2011 study found that constitutive activation occurred only with overexpression and of wild-type RANK as much as mutant, that at low expression the mutant receptor neither activated NF-kappaB constitutively nor responded to ligand, and that the mutant protein sits in the endoplasmic reticulum rather than at the membrane; it concluded that the disease cannot be explained by the mutant receptor alone. The knock-in mouse then showed that two mutant alleles abolish osteoclasts while one mutant allele beside a wild-type one prolongs osteoclast survival without RANKL, which is compatible with either a dominant effect of the misfolded protein on the cell or an interaction with wild-type receptor, and with neither simple model. Reviews have proposed an unfolded-protein-response route to NF-kappaB, which has not been tested in osteoclasts. The question matters for treatment: if signalling is truly ligand-independent, RANKL blockade should be ineffective, and the single denosumab response argues the other way. Every functional study to date has used the 27-bp or heterologous overexpression systems; no patient-derived osteoclast study of the 18-bp allele has been published.

Proposed experiments

NF-kappaB and unfolded-protein-response signalling in heterozygous 84dup18 osteoclasts

feo_patient_osteoclast_84dup18_signalling

Differentiate osteoclasts from peripheral blood monocytes or iPSC-derived precursors of FEO patients carrying 84dup18, and from isogenic corrected controls, and measure basal and RANKL-stimulated NF-kappaB activity, osteoclast survival without RANKL, and unfolded-protein-response markers. A cell that shows basal NF-kappaB activity with UPR induction and no RANKL dose-response supports the misprocessing model; one that shows a shifted RANKL dose-response supports an interaction of mutant with wild-type receptor.

Would support

pathophysiology#Ligand-Independent RANK Signalling and NF-kappaB Activation

Supporting outcome

Basal NF-kappaB activity in heterozygous patient osteoclasts at endogenous expression levels, absent in isogenic controls.

Refuting outcome

No basal NF-kappaB activity, with prolonged survival explained by a pathway other than NF-kappaB.

Knock-in mouse carrying the FEO 18-bp duplication

feo_84dup18_knock_in_mouse

Generate a Tnfrsf11a 84dup18 knock-in and compare the heterozygous skeletal, ossicular and dental phenotype with the 75dup27 line, to test whether the length of the signal-peptide extension determines the lytic versus Paget-like pattern and whether the homozygous osteopetrosis is general to the allelic series.

Show evidence (3 references)

PMID:21472776 SUPPORT In Vitro

"These results strongly suggest that the increased osteoclast formation/activity caused by these mutations cannot be explained by studying the homozygous phenotype alone but requires further detailed investigation of the heterozygous expression of the mutant RANK proteins."

The authors' own statement of the gap: the heterozygous state, not the mutant receptor alone, holds the explanation.

PMID:20458572 SUPPORT Other

"Whole animal studies replicate the hyperactive osteoclast phenotype associated with these disorders and present only with heterozygous expression of the mutation, suggesting an as yet unexplained effect of the mutant allele on normal RANK function."

A review names the unexplained effect of the mutant allele on normal RANK function as the open question. Evidence source is OTHER.

PMID:33724536 SUPPORT Model Organism

"In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation."

The homozygous result that excludes a simply hyperactive receptor and keeps the gap open.

Does RANKL blockade with denosumab control the osteoclast overactivity of FEO, and if so what does that say about the ligand dependence of signalling from the mutant receptor?

KNOWLEDGE GAP OPEN feo_denosumab_ligand_dependence

Attached to

treatments#Denosumab pathophysiology#Ligand-Independent RANK Signalling and NF-kappaB Activation

The mechanism curated above is described as ligand-independent, and the ER-retained mutant receptor cannot be activated by ligand in vitro, which would predict that neutralising RANKL does little. Against that, one adult with FEO treated with denosumab in 2025 showed radiological improvement, better quality of life and enough control to permit limb salvage. A response to ligand blockade implies that osteoclast activity in FEO retains a RANKL-dependent component, most plausibly through the wild-type receptor in the same heterozygous cell. One case cannot settle it, and the knock-in mouse's osteoclasts survived without RANKL, which predicts a partial rather than complete response. The question is practical: bisphosphonates act on the osteoclast regardless of the receptor's state, denosumab does not.

Proposed experiments

Prospective turnover-marker response to denosumab in FEO

feo_denosumab_turnover_marker_series

Treat a small series of adults with molecularly confirmed FEO with denosumab under a hypocalcaemia protocol and measure bone resorption markers and lesion scintigraphic activity before and after, comparing the depth of suppression with that achieved by zoledronic acid in the same patients. Complete suppression implies fully ligand-dependent osteoclast activity; partial suppression quantifies the ligand-independent component.

Show evidence (2 references)

PMID:41264685 SUPPORT Human Clinical

"The use of denosumab for FEO displays improvement in radiological appearances of the affected bone, increased quality of life and may prevent the development of further lesions."

The single response that raises the question.

PMID:21472776 SUPPORT In Vitro

"In conclusion, signal peptide mutations lead to accumulation of RANK in the endoplasmic reticulum and prevent direct activation by RANK ligand."

The in vitro finding that predicts ligand blockade should not act on the mutant receptor itself.

How far does the Tnfrsf11a 75dup27 knock-in mouse, which carries the early-onset Paget allele, model the lytic, expansile, appendicular disease and the ossicular and dental resorption of the human 18-bp duplication?

HUMAN MODEL MISMATCH OPEN feo_mouse_allele_mismatch

Attached to

pathophysiology#Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning pathophysiology#Middle-Ear Ossicular Resorption pathophysiology#External Root Resorption of Permanent Teeth

The model reproduces focal, age-dependent, drug-preventable osteolysis from a heterozygous signal-peptide duplication, which is strong evidence for the shared mechanism. What it does not do is carry the FEO allele: the 27-bp duplication produces a Paget-like lytic-sclerotic disease with jaw and skull involvement in humans, where the 18-bp duplication produces purely lytic limb lesions that end in fat-filled bone. Duplication length appears to matter to phenotype in the human allelic series, so an inference from one allele to another is an inference across the very variable that separates the disorders. The abstract reports no hearing or dental phenotype, so the two earliest human manifestations are unmodelled. This is recorded as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the model evidence exists and is good; what is open is its transfer to the specific human allele.

Proposed experiments

Ossicular and dental phenotyping of the 75dup27 heterozygous mouse

feo_75dup27_mouse_ossicle_and_tooth_phenotyping

Micro-CT of the auditory ossicles and molar roots in heterozygous 75dup27 mice across age, with auditory brainstem responses, to test whether the earliest human manifestations of the signal-peptide duplication are present in the existing model before an 18-bp line is made.

Show evidence (2 references)

PMID:33724536 SUPPORT Model Organism

"To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB."

Identifies the allele modelled as the early-onset Paget one.

PMID:12929927 SUPPORT Human Clinical

"We conclude that the 75dup27 mutation of RANK causes a Paget's disease of bone-like phenotype that is distinct from, but which overlaps with, FEO and ESH."

The human phenotype of the modelled allele is distinct from FEO, which is the substance of the mismatch.

⚙

Pathophysiology

8

TNFRSF11A Exon 1 Signal-Peptide Tandem Duplication

The initiating lesion. A heterozygous in-frame 18-base-pair tandem duplication in exon 1 of TNFRSF11A, the gene encoding receptor activator of NF-kappaB (RANK), inserts six amino acids into the signal peptide of the receptor. The classic allele is 84dup18; a second 18-bp duplication one base proximal to it adds the same six residues. Intragenic haplotypes show that the identical duplication has arisen independently at least three times, and the exon 1 sequence can form a stable secondary structure that may favour tandem duplication, which is why the same lesion recurs in unrelated families. The allelic 27-, 15- and 12-bp duplications in the same signal peptide cause the related disorders described in the notes.

TNFRSF11A hgnc:11908

Genetic context TNFRSF11A hgnc:11908 allele_type: in-frame 18-bp tandem duplication in exon 1 (signal peptide) variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Classified as gain of function on the basis of the original functional characterisation, in which both signal-peptide duplications increased RANK-mediated NF-kappaB signalling in vitro, and on the heterozygous disease phenotype of excessive osteoclast activity. The category is held with the caveat recorded in the knowledge gap below: the mutant receptor by itself cannot be activated by ligand, and how one mutant allele overactivates osteoclasts in heterozygous cells is unresolved.

Downstream

Failure of RANK Signal-Peptide Cleavage and Endoplasmic Reticulum Retention Lengthening the signal peptide prevents its cleavage, so the receptor is not processed through the secretory pathway normally.

Show evidence (7 references)

PMID:10615125 SUPPORT Human Clinical

"We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB)."

The discovery of the causal lesion: heterozygous exon 1 insertions in affected members of four families.

PMID:10615125 SUPPORT Human Clinical

"One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule."

Identifies the 18-bp duplication as the FEO allele and locates both duplications in the signal peptide.

PMID:12568416 SUPPORT Human Clinical

"Mutational analysis of the TNFRSF11A gene in our patients demonstrated an 18 base pair tandem duplication, one base proximal to the duplications previously reported."

The second 18-bp allele, shifted by one base, in two unrelated patients.

+ 4 more references

Failure of RANK Signal-Peptide Cleavage and Endoplasmic Reticulum Retention

The elongated signal peptide is not removed. In two independent in vitro translation systems the mutant proteins fail signal-peptide cleavage, and when expressed in cells mutant RANK does not reach the plasma membrane but accumulates in extensive areas of organised smooth endoplasmic reticulum, where wild-type RANK is found at the membrane and in the Golgi. Reviews describe the consequence as the protein translated from the mutant allele being trapped in the endoplasmic reticulum. The mutant receptor that does accumulate cannot be activated by RANK ligand, so whatever it does to the cell, it does not do it by responding to ligand in the ordinary way.

retention of mutant RANK in the endoplasmic reticulum GO:0035437 ↑ INCREASED

endoplasmic reticulum GO:0005783

Downstream

Ligand-Independent RANK Signalling and NF-kappaB Activation The step that is inferred rather than demonstrated. The retained, ligand-unresponsive mutant receptor is nonetheless associated with increased NF-kappaB signalling in the discovery study and with overactive osteoclasts in patients; the route, whether self-association of misfolded receptor, an unfolded-protein response, or an effect of the mutant allele on the wild-type receptor in the same cell, is unresolved.

Show evidence (4 references)

PMID:21472776 SUPPORT In Vitro

"This intracellular accumulation of the mutant proteins is probably the result of lack of signal peptide cleavage because, using two in vitro translation systems, we demonstrate that the mutations in RANK prevent cleavage of the signal peptide."

Direct demonstration that the duplications prevent signal-peptide cleavage, and the authors' link from that failure to intracellular accumulation.

PMID:21472776 SUPPORT In Vitro

"When overexpressed, mutant RANK did not localize to the plasma membrane but localized to extensive areas of organized smooth endoplasmic reticulum, whereas, as expected, wild-type RANK was detected at the plasma membrane and in the Golgi apparatus."

The localisation result behind the endoplasmic-reticulum retention in this node's name.

PMID:21472776 SUPPORT In Vitro

"Importantly, only cells expressing wild-type RANK demonstrated ligand-dependent activation of NF-κB."

The retained mutant receptor is not ligand-responsive, which constrains every downstream explanation of the disease.

+ 1 more reference

Ligand-Independent RANK Signalling and NF-kappaB Activation

RANK signalling that is no longer under the control of RANK ligand. In the discovery study, recombinant mutant RANK increased RANK-mediated NF-kappaB signalling in vitro relative to wild type, and the mutations were read as activating; reviews state the mechanism as osteoclast activation through NF-kappaB independent of ligand. The later study of stably transfected cells found that constitutive activation occurred only with overexpression, of wild-type as well as mutant RANK, and not at low expression levels, and concluded that the disease cannot be explained by the mutant receptor alone. The modifier is recorded as GAIN_OF_FUNCTION rather than INCREASED because the claim is qualitative: the pathway has escaped its ligand, not merely risen above its normal level. The disagreement about how it escaped is the entry's knowledge gap.

ligand-independent RANK-mediated NF-kappaB signalling GO:0007249 ⇑ GAIN OF FUNCTION tumour necrosis factor receptor superfamily (RANK) signalling GO:0033209 ↕ DYSREGULATED

Downstream

Constitutive Osteoclast Formation, Survival and Activation RANK signalling into NF-kappaB is the pathway that instructs osteoclast differentiation, survival and activity, so signalling that has escaped ligand control produces osteoclasts that are not under the skeleton's normal regulation.

Show evidence (4 references)

PMID:10615125 SUPPORT In Vitro

"Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation."

The original activating-mutation interpretation on which the gain of function classification rests.

PMID:30756140 SUPPORT Other

"The mutations interfere with normal processing of RANK and cause osteoclast activation through activation of nuclear factor kappa B (NFκB) independent of RANK ligand stimulation."

A review states the ligand-independent NF-kappaB activation that names this node. Evidence source is OTHER because this is a review.

PMID:21472776 REFUTE In Vitro

"We show here that constitutive activation of NF-κB occurred in HEK293 cells overexpressing wild-type or mutant RANK but not in stably transfected cell lines expressing low levels of each RANK gene."

Recorded as REFUTE of the simple constitutive-activation model: at physiological expression levels the mutant receptor did not activate NF-kappaB, and overexpression activated it regardless of mutation.

+ 1 more reference

Constitutive Osteoclast Formation, Survival and Activation

Osteoclasts form, persist and resorb in excess of what the skeleton has asked for. Affected bone shows increased osteoclast and osteoblast activity, and the mouse carrying the allelic 75dup27 duplication shows what the heterozygous state does to the lineage: RANKL-induced osteoclast formation and signalling in marrow cells is impaired, yet osteoclast survival is increased independently of RANKL, and the animals develop focal osteolytic lesions. The same allele in homozygous form abolishes osteoclasts altogether and causes osteopetrosis, which shows that the mutant receptor is not simply hyperactive but that one mutant allele beside a wild-type one changes osteoclast behaviour in a way that neither allele alone explains. This node conforms to the module's RANKL-driven osteoclastogenesis step with the substitution that the driver is a receptor escaped from ligand control rather than an excess of ligand.

osteoclast CL:0000092

osteoclast differentiation GO:0030316 ↑ INCREASED osteoclast survival (reduced apoptosis) GO:0043066 ↑ INCREASED

Animal models

Tnfrsf11a 75dup27 heterozygous knock-in mouse Mouse partially recapitulates Shows the heterozygous osteoclast phenotype: RANKL-driven formation is impaired, yet survival is prolonged without RANKL and lesions form in vivo, which is the paradox this node carries.

Tnfrsf11a 75dup27 homozygous knock-in mouse Mouse fails to recapitulate Two copies of the mutant allele produce the opposite of the human disease at the osteoclast: no osteoclasts at all.

Downstream

Generalized Accelerated Bone Remodelling Excess osteoclast activity throughout the skeleton, with coupled osteoblast activity, raises the rate of bone remodelling everywhere.

Show evidence (4 references)

PMID:10615125 SUPPORT Human Clinical

"The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity."

The histological observation in patients that both osteoclast and osteoblast activity are increased in lesions, which is why this is a high-turnover rather than a formation-deficient disease.

PMID:33724536 SUPPORT INDIRECT Model Organism

"This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling."

The clearest cellular statement of what a heterozygous signal-peptide duplication does to osteoclasts: it extends their survival without RANKL. Indirect because the allele is the PDB2 27-bp duplication, not the FEO 18-bp one.

PMID:33724536 SUPPORT INDIRECT Model Organism

"In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation."

The homozygous result that rules out a simple hyperactive receptor and makes the heterozygous interaction the object of the mechanism.

+ 1 more reference

Generalized Accelerated Bone Remodelling

Bone turnover runs fast across the whole skeleton, not only at the focal lesions. Bone scintigraphy shows increased uptake at multiple foci, serum alkaline phosphatase and urinary hydroxyproline are variably elevated while other biochemical indices stay normal, and the skeleton as a whole is osteopenic. The focal osteolytic lesions of the limbs, the ossicular resorption of the middle ear and the external root resorption of the teeth are three site-specific expressions of this generalised state.

osteoclast CL:0000092 osteoblast CL:0000062

bone remodeling GO:0046849 ↑ INCREASED

Downstream

Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning At scattered sites in the long bones, resorption escapes even the accelerated coupling and produces an advancing lytic lesion.

Middle-Ear Ossicular Resorption The auditory ossicles are small bones subject to the same osteoclast overactivity, and are resorbed early.

External Root Resorption of Permanent Teeth Osteoclast-lineage odontoclasts resorb the cervical and apical root of the permanent teeth.

Elevated serum alkaline phosphatase The osteoblastic arm of accelerated remodelling releases alkaline phosphatase into serum.

Generalized osteopenia Net loss of bone across the skeleton from remodelling that resorbs faster than it refills.

Show evidence (4 references)

PMID:3346299 SUPPORT Human Clinical

"The disease shows both general and focal skeletal changes, the latter being mainly in the limbs with an onset from the second decade."

The original description separates the generalised skeletal change from the focal limb lesions, which is the distinction this node and the next one make.

PMID:3346299 SUPPORT Human Clinical

"The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."

The turnover markers that read out the generalised remodelling.

PMID:15793411 SUPPORT Human Clinical

"There was an increase in uptake and activity at multiple foci of the whole skeleton."

Whole-body scintigraphy showing multifocal increased activity, the imaging correlate of generalised remodelling.

+ 1 more reference

Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning

The defining skeletal lesion. From the second decade, focal osteolytic lesions arise mainly in the limb bones, the tibia above all, and advance along the shaft. Progressive osteoclastic resorption is accompanied by medullary expansion and cortical thinning, so the bone widens as it weakens; the sequence ends in pain, severe deformity and pathological fracture. Unlike Paget disease, the lesion does not pass into a sclerotic phase: osteolysis progresses to fat-filled bone. Extensive peripheral and even skull involvement has been described in childhood-onset disease. Conforms to the module's central resorption effector with the caveat that here the resorption is focal and expansile rather than the diffuse trabecular loss of osteoporosis.

osteoclast CL:0000092

bone resorption GO:0045453 ↑ INCREASED

long bones of the limbs UBERON:0002495 tibia UBERON:0000979

Animal models

Tnfrsf11a 75dup27 heterozygous knock-in mouse Mouse partially recapitulates Reproduces age-dependent focal osteolytic lesions of the limb bones from a heterozygous signal-peptide duplication, which is the defining lesion of this node.

Downstream

Focal expansile osteolytic lesions of the long bones The radiographic phenotype of this node.

Bone pain Pain localised to active lesions.

Pathologic fracture Cortical thinning and expansion leave the bone unable to carry load.

Long bone deformity and bowing Expanded, thinned bone deforms under load.

Show evidence (5 references)

PMID:3346299 SUPPORT Human Clinical

"Progressive osteoclastic resorption is accompanied by medullary expansion which leads to pain, severe deformity and a tendency to pathological fracture."

The original statement of the lesion's structure and its consequences, naming osteoclastic resorption, medullary expansion, pain, deformity and fracture in one sentence.

PMID:10615125 SUPPORT Human Clinical

"The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity."

Localises the lesions to the long bones and dates their onset.

PMID:12568416 SUPPORT Human Clinical

"Familial expansile osteolysis (FEO) is a rare autosomal dominant disorder characterized by striking focal expansile osteolytic bone lesions and generalized osteopenia, often accompanied by characteristic early hearing loss and dental disease."

Names the focal expansile osteolytic lesion as the characteristic feature against the generalised osteopenic background.

+ 2 more references

Middle-Ear Ossicular Resorption

The auditory ossicles are resorbed. Hereditary incus necrosis was the first ossicular lesion described in the Northern Irish family; a later family showed total absence of the middle-ear ossicles on temporal-bone CT and at exploratory surgery, with the hearing loss dating from childhood. Because the ossicles are among the smallest bones in the body, the same osteoclast overactivity that takes decades to hollow a tibia can remove them in the first years of life, which is why deafness is usually the first sign of the disease. The loss is conductive; a mixed component develops in some patients. Ossicular reconstruction has been reported not to improve thresholds.

osteoclast CL:0000092

bone resorption GO:0045453 ↑ INCREASED

auditory ossicles UBERON:0001686 middle ear UBERON:0001756

Downstream

Early-onset conductive and mixed hearing loss Loss of the ossicular chain breaks sound conduction to the cochlea.

Absent or resorbed middle-ear ossicles The imaging and surgical finding of this node.

Show evidence (3 references)

PMID:15793411 SUPPORT Human Clinical

"The total absence of middle-ear ossicles can probably be regarded as a new symptom in some patients with familial expansile osteolysis."

The extreme of the ossicular lesion: complete absence of the ossicles in three members of one family.

PMID:15793411 SUPPORT Human Clinical

"Hearing loss was revealed in the medical histories since childhood."

Dates the ossicular lesion to childhood.

PMID:2530018 SUPPORT Human Clinical

"Most affected members of the family have an associated early-onset deafness and loss of dentition as a result of unique middle ear and dental abnormalities."

Attributes the early deafness to a middle-ear abnormality in the original kindred.

External Root Resorption of Permanent Teeth

Cervical and apical external resorption of the roots of the permanent teeth, with premature deposition of irregular secondary dentine that narrows the pulp and of cellular cementum that narrows the periodontal ligament. Root resorption is an early manifestation, present in 16 of 20 family members with skeletal disease in the Northern Irish study, and may precede bone involvement; the deciduous teeth are largely spared. The teeth loosen, fracture and are lost in adolescence. It is the dental expression of the same resorptive overactivity, and in a child it can be the presenting finding.

bone resorption (root and periodontal resorption) GO:0045453 ↑ INCREASED

roots of the permanent teeth UBERON:0001091

Downstream

External root resorption of permanent teeth The dental phenotype of this node.

Premature loss of permanent teeth Resorbed roots loosen and the teeth are lost.

Show evidence (3 references)

PMID:2216357 SUPPORT Human Clinical

"Twenty-seven family members, aged 3 to 60 years, were examined clinically and radiographically, and it was found that cervical and/or apical root resorption is an early manifestation of the dysplasia."

The clinical and radiographic dental study of the original kindred, establishing root resorption as an early manifestation.

PMID:2216357 SUPPORT Human Clinical

"Of the 20 family members with skeletal manifestations of familial expansile osteolysis, 16 showed root resorption."

The count behind the frequency of root resorption in affected members.

PMID:2341974 SUPPORT Human Clinical

"The predominant dental features are resorption of the cervical and apical regions of the roots, premature depositions both of irregular secondary dentin, which causes narrowing of the pulp cavities, and of cellular cementum, which causes patchy narrowing of the periodontal ligament."

The histopathology of the dental lesion, showing that the tooth is remodelled as well as resorbed.

✶

Histopathology

2

Osteoclast-rich resorption with increased osteoclast number and multinuclearity

Affected bone shows an increase in osteoclast number, in the number of nuclei per osteoclast and in osteoclast activity, with coupled osteoblast activity, the histological picture of a high-turnover osteoclast-driven lesion. This is the tissue basis of the pathophysiology node "Constitutive Osteoclast Formation, Survival and Activation". The bound NCIT term covers the increase in osteoclast number; the multinuclearity and activity components are carried by the preferred term and the quoted evidence.

Show evidence (2 references)

PMID:10615125 SUPPORT Human Clinical

"The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity."

The histological observation in patients' lesions of increased osteoclast and osteoblast activity.

PMID:21472776 SUPPORT BACKGROUND Human Clinical

"Affected areas show an increase in osteoclast number, multinuclearity, and activity, which leads to the notion that these diseases are driven by osteoclast overactivity, as is classic late-onset Paget disease of bone."

The count, multinuclearity and activity components of the finding. The sentence is the introduction's summary of the published human histology of the RANK signal-peptide disorders rather than a result of the paper's own in vitro experiments, so the evidence it describes is human clinical and the quote role records that this paper is not its source.

Fibrous and then fatty replacement of the medulla at the end stage of a lesion

The advancing lytic lesion destroys the medullary bone, which is replaced first by fibrous tissue and finally by fat, so that the burnt-out lesion is a thin-walled, fat-filled shell rather than the sclerotic bone of a late Paget lesion. The same fibrous replacement is seen in the middle ear, where the incus is replaced by fibrous tissue. Left unbound because no NCIT morphologic-finding term covers the fibrous-to-fatty sequence of medullary replacement: NCIT:C36212 (Bone Marrow Fibrosis) is in the histopathology branch but names only the fibrous stage, and binding it would misdescribe the fat-filled end state that defines the finding. The two sources quoted are a radiographic series and a review, and the finding is recorded here because it is the tissue end state the radiographs and the reviews describe.

Show evidence (3 references)

PMID:2353208 SUPPORT Human Clinical

"Focal features comprise lytic areas which progressively enlarge, producing expansion of the bone and eventual disintegration due to fibrous and finally fatty replacement of the normal medulla."

The radiographic series of the original kindred describes the sequence of fibrous and then fatty replacement of the medulla.

PMID:16831914 SUPPORT Other

"In FEO, osteolysis progresses to fat-filled bone rather than to osteosclerosis."

Review statement of the fat-filled end state and its contrast with Paget sclerosis. Evidence source is OTHER because this is a review.

PMID:30756140 SUPPORT Other

"A characteristic feature on otological examination was replacement of the incus by fibrous tissue."

The fibrous replacement of resorbed bone seen at the incus. Evidence source is OTHER because this is a review.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

12

Ear 2

Early-onset conductive and mixed hearing loss VERY_FREQUENT Conductive hearing impairment HP:0000405

Onset: CHILDHOOD

Show evidence (3 references)

PMID:3346299 SUPPORT Human Clinical

"Most patients had an associated deafness of early onset and loss of dentition."

Establishes both the early-onset deafness and its frequency: most patients in the 40-case kindred, which supports VERY_FREQUENT.

PMID:15793411 SUPPORT Human Clinical

"Audiometry indicated mild to moderate conductive and mixed hearing loss and also an AD-type tympanogram pattern along with an absence of acoustic reflexes in both ears of the cases."

Audiometric characterisation as conductive and mixed loss.

PMID:12568416 SUPPORT Human Clinical

"One had no family history of FEO, but presented with bilateral hearing loss at an early age, deterioration of teeth, and severe pain and swelling in the distal tibia before the age of 20."

A sporadic case presenting with early bilateral hearing loss, showing the feature is not confined to the Northern Irish kindred.

Absent or resorbed middle-ear ossicles Abnormality of the middle ear ossicles HP:0004452

Show evidence (2 references)

PMID:15793411 SUPPORT Human Clinical

"The temporal-bone computed-tomography scan in the coronal view of all three patients and also exploratory middle-ear surgery, which was done on two of the patients, showed no ossicles in the middle ear of either ear in all three cases."

The imaging and surgical demonstration of complete ossicular absence.

PMID:2530018 SUPPORT Human Clinical

"Most affected members of the family have an associated early-onset deafness and loss of dentition as a result of unique middle ear and dental abnormalities."

Attributes the deafness of the original kindred to a middle-ear abnormality.

Genitourinary 1

Hydroxyprolinuria HP:0003080

Show evidence (2 references)

PMID:3346299 SUPPORT Human Clinical

"The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."

Names urinary hydroxyproline as variably elevated.

PMID:2530018 SUPPORT Human Clinical

"The serum alkaline phosphatase and urinary hydroxyproline are elevated to a variable degree, whereas other biochemical indices are normal."

The 1989 description restates the elevated urinary hydroxyproline.

Head and Neck 2

External root resorption of permanent teeth VERY_FREQUENT Abnormal dental root morphology HP:0006486

Show evidence (3 references)

PMID:2216357 SUPPORT Human Clinical

"Of the 20 family members with skeletal manifestations of familial expansile osteolysis, 16 showed root resorption."

Sixteen of twenty affected members, 80 per cent, which supports the VERY_FREQUENT band.

PMID:2216357 SUPPORT Human Clinical

"Root resorption may therefore be a good prognosticator for later bone involvement."

Root resorption precedes and predicts skeletal disease.

PMID:32075714 SUPPORT Human Clinical

"The patient was not diagnosed with FEO until the age of 10 years, when she presented to the dental clinic with advanced ERR in several permanent teeth."

A child in whom advanced external root resorption was the presenting finding.

Premature loss of permanent teeth VERY_FREQUENT Premature loss of teeth HP:0006480

Show evidence (2 references)

PMID:3346299 SUPPORT Human Clinical

"Most patients had an associated deafness of early onset and loss of dentition."

Loss of dentition in most patients of the 40-case kindred, supporting the VERY_FREQUENT band.

PMID:17447113 SUPPORT Human Clinical

"The clinical features of FEO include early-onset hearing loss, tooth destruction, and progressive lytic expansion within limb bones causing pain, fracture, and deformity."

Tooth destruction as a cardinal clinical feature.

Metabolism 1

Elevated serum alkaline phosphatase Elevated circulating alkaline phosphatase concentration HP:0003155

Show evidence (2 references)

PMID:3346299 SUPPORT Human Clinical

"The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."

The original biochemical description: variably elevated alkaline phosphatase with other indices normal.

PMID:15793411 SUPPORT Human Clinical

"Both serum alkaline phosphatase and hydroxyproline levels were elevated."

Elevated alkaline phosphatase in a second, unrelated family.

Musculoskeletal 5

Focal expansile osteolytic lesions of the long bones Osteolysis HP:0002797

Course: PROGRESSIVE Onset: JUVENILE

Show evidence (3 references)

PMID:3346299 SUPPORT Human Clinical

"The disease shows both general and focal skeletal changes, the latter being mainly in the limbs with an onset from the second decade."

Places the focal lesions in the limbs and dates their onset to the second decade.

PMID:17447113 SUPPORT Human Clinical

"The clinical features of FEO include early-onset hearing loss, tooth destruction, and progressive lytic expansion within limb bones causing pain, fracture, and deformity."

Names progressive lytic expansion within the limb bones as a cardinal clinical feature.

PMID:16470392 SUPPORT Human Clinical

"This case documents that familial expansile osteolysis is not only a disease of adults but does occur in childhood."

Extends the onset range into childhood.

Pathologic fracture HP:0002756

Show evidence (2 references)

PMID:3346299 SUPPORT Human Clinical

"Progressive osteoclastic resorption is accompanied by medullary expansion which leads to pain, severe deformity and a tendency to pathological fracture."

Names the tendency to pathological fracture as a consequence of the lesion.

PMID:2530018 SUPPORT Human Clinical

"Progressive osteoclastic resorption accompanied by medullary expansion leads to severe and painful disabling deformities with a tendency to pathologic fracture."

The 1989 kindred description restates fracture as part of the natural history.

Long bone deformity and bowing Abnormal long bone morphology HP:0011314

Course: PROGRESSIVE

Show evidence (2 references)

PMID:2530018 SUPPORT Human Clinical

"Progressive osteoclastic resorption accompanied by medullary expansion leads to severe and painful disabling deformities with a tendency to pathologic fracture."

Describes the deformities as severe and disabling.

PMID:17447113 SUPPORT Human Clinical

"The clinical features of FEO include early-onset hearing loss, tooth destruction, and progressive lytic expansion within limb bones causing pain, fracture, and deformity."

Names deformity among the consequences of lytic expansion in the limb bones.

Generalized osteopenia HP:0000938

Show evidence (1 reference)

PMID:12568416 SUPPORT Human Clinical

"Familial expansile osteolysis (FEO) is a rare autosomal dominant disorder characterized by striking focal expansile osteolytic bone lesions and generalized osteopenia, often accompanied by characteristic early hearing loss and dental disease."

Names generalised osteopenia as a characteristic feature alongside the focal lesions.

Osteosarcoma HP:0002669

Show evidence (2 references)

PMID:20168251 SUPPORT Human Clinical

"We present the first reported case of a child with familial expansile osteolysis syndrome (FEO) who developed osteogenic sarcoma (OS) of the iliac bone."

The first reported case; the title's question mark and the single case are why this phenotype carries no frequency.

PMID:20168251 SUPPORT Human Clinical

"We also think that increased bone turnover, characteristic of a condition such as FEO, may facilitate de novo development of OS."

The authors' mechanistic speculation, recorded as speculation.

Constitutional 1

Bone pain HP:0002653

Show evidence (2 references)

PMID:3346299 SUPPORT Human Clinical

"Progressive osteoclastic resorption is accompanied by medullary expansion which leads to pain, severe deformity and a tendency to pathological fracture."

Names pain as a consequence of the expanding lesion.

PMID:41264685 SUPPORT Human Clinical

"Familial expansile osteolysis (FEO) is a rare inherited autosomal dominant condition causing the development of painful lytic bone lesions."

A recent case report characterises the lesions as painful.

🧬

Genetic Associations

1

TNFRSF11A (Causative)

Gene: TNFRSF11A hgnc:11908 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (7 references)

PMID:10615125 SUPPORT Human Clinical

"We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB)."

The gene discovery in affected members of four families.

PMID:10615125 SUPPORT Human Clinical

"RANK is essential in osteoclast formation."

The function of the gene product that makes the lesion an osteoclast disease.

PMID:12568416 SUPPORT Human Clinical

"Identical insertional mutations in the first exon of RANK have been identified in all published FEO kindreds."

The recurrence of the same mutation across all kindreds published to 2003.

+ 4 more references

💊

Medical Actions

5

Bisphosphonate Therapy

Action: Bisphosphonate Therapy NCIT:C198585

Agent: zoledronic acid CHEBI:46557 pamidronate CHEBI:7903 alendronate CHEBI:2567

Platform: Small molecule

Nitrogen-containing bisphosphonates are the mainstay. Intravenous zoledronic acid or pamidronate, or oral alendronate, suppress the biochemical markers of turnover for prolonged periods and in the allelic disorders have mineralised early lesions and improved bone density; the first-generation agents etidronate and clodronate gave only transient responses, which is why aminobisphosphonates are preferred. Whether treatment changes the natural history of established lesions, deafness or tooth loss is uncertain: in early-onset Paget disease the biochemical response was not matched by clinical benefit for deformity, deafness or tooth loss, and the strongest argument for early treatment is a single child with a 12-bp duplication who developed no focal lesions on alendronate. In the 75dup27 mouse, zoledronic acid completely prevented lesion development. The specific hazard is prolonged hypocalcaemia after potent intravenous dosing in a high-turnover skeleton, so calcium and vitamin D are replete before treatment and calcium is monitored after it.

Mechanism Target:

INHIBITS Constitutive Osteoclast Formation, Survival and Activation — Bisphosphonates act on the osteoclast directly, inducing its apoptosis and inhibiting resorption downstream of RANK, so they bypass the question of whether the receptor's signalling is ligand-dependent.

Show evidence (2 references)

PMID:33724536 SUPPORT INDIRECT Model Organism

"Treatment of these mice with zoledronic acid completely prevented the development of lesions."

Prevention of focal lesions by an osteoclast-targeted drug in the knock-in mouse; indirect because the allele is the PDB2 duplication.

PMID:30756140 SUPPORT Other

"Bisphosphonates have been successfully used to gain control of elevated bone remodelling but as yet, no effective treatment exists for the treatment of the muscle and neurological manifestations of MSP syndromes."

Review conclusion that bisphosphonates control the elevated remodelling in these disorders. Evidence source is OTHER because this is a review.

Show evidence (8 references)

PMID:16831914 SUPPORT Other

"Antiresorptive therapy with bisphosphonates can be effective for each disorder."

Review statement covering FEO and its allelic disorders. Evidence source is OTHER because this is a review.

PMID:18328984 SUPPORT Other

"Anecdotal reports indicate that osteoclast inhibitors such as bisphosphonates are effective for suppressing bone turnover and improving symptoms in these disorders, although the long-term effects on clinical outcomes are unclear."

Both the efficacy on turnover and the uncertainty about long-term clinical outcome, from a review. Evidence source is OTHER.

PMID:36740137 SUPPORT INDIRECT Human Clinical

"Bisphosphonate treatment, initiated with one dose of intravenous zoledronic acid that caused prolonged hypocalcemia, then comprised weekly oral alendronate that decreased bone turnover markers and normalized her BMD."

The zoledronate hypocalcaemia hazard and the alendronate response in one sentence. Indirect because the child carried the allelic 12-bp duplication.

+ 5 more references

Denosumab

Action: Pharmacotherapy NCIT:C15986

Agent: denosumab NCIT:C61313

Platform: Monoclonal antibody

The anti-RANKL monoclonal antibody, reported in a single adult with FEO in 2025, in whom it improved the radiological appearance of affected bone and quality of life and permitted limb-salvage surgery in place of amputation. Its use is mechanistically interesting rather than established: if the mutant receptor signals independently of ligand, blocking the ligand should do little, so a response implies that osteoclast activity in FEO retains a RANKL-dependent component. The same hypocalcaemia caution as for bisphosphonates applies, and rebound turnover on withdrawal is a known property of the drug in other settings.

Mechanism Target:

INHIBITS Constitutive Osteoclast Formation, Survival and Activation — Neutralises RANKL, removing the ligand-dependent contribution to osteoclast formation and survival. The size of that contribution in FEO is the open question recorded in the discussions.

Show evidence (1 reference)

PMID:41264685 SUPPORT Human Clinical

"The use of denosumab for FEO displays improvement in radiological appearances of the affected bone, increased quality of life and may prevent the development of further lesions."

A radiological and clinical response in one patient, which is the whole of the evidence that ligand blockade acts on the lesion.

Show evidence (2 references)

PMID:41264685 SUPPORT Human Clinical

"We present the case of a 54-year-old man with FEO who was treated with denosumab."

The single published use of denosumab in FEO.

PMID:41264685 SUPPORT Human Clinical

"It is a safe treatment modality for patients with FEO that allows for limb salvage surgery rather than amputation."

The authors' conclusion on safety and on enabling limb salvage; a single-case conclusion, recorded as such.

Orthopaedic Stabilisation and Limb Salvage Surgery

Action: orthopaedic stabilisation and limb salvage surgery Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

Fracture fixation, stabilisation or correction of deformed expanded bones, and limb-salvage reconstruction for lesions that have destroyed the shaft. Historically, severe disease led to amputation; the 2025 denosumab case reports that antiresorptive control made limb salvage possible instead. Surgery on active lesions has been observed to accelerate their extension, so operations are planned with turnover controlled where possible.

Target Phenotypes: Pathologic fracture HP:0002756 Progressive deformity of the affected long bones HP:0011314

Show evidence (1 reference)

PMID:41264685 SUPPORT Human Clinical

"It is a safe treatment modality for patients with FEO that allows for limb salvage surgery rather than amputation."

Places limb salvage surgery, and amputation as its historical alternative, in the management of advanced lesions.

Hearing Rehabilitation with Cochlear Implantation

Action: cochlear device implantation and auditory rehabilitation Ontology label: Surgical Procedure NCIT:C15329

Platform: Device

Amplification and, for profound or mixed loss, cochlear implantation. Ossicular reconstruction is the intuitive operation for a conductive loss but has not improved thresholds where the ossicles are absent, and surgeons are warned of that. A child with an allelic 12-bp duplication was implanted at age 3 after conductive and sensorineural loss was found on evaluation for speech delay. The device is carried as a qualifier so that the cochlear implant remains queryable while the bound term stays a clinical action.

Target Phenotypes: Early-onset conductive, later mixed, hearing loss HP:0000405

Show evidence (3 references)

PMID:36740137 SUPPORT INDIRECT Human Clinical

"Speech delay was identified at age 18 months, and audiological evaluation showed both conductive and sensorineural hearing loss subsequently treated with a cochlear implant at age 3 years."

Cochlear implantation for the hearing loss of a TNFRSF11A signal-peptide duplication; indirect because the child carried the allelic 12-bp allele rather than the FEO allele.

PMID:15793411 REFUTE Human Clinical

"No improvement in hearing thresholds was obtained after reconstruction of the middle ear."

Recorded as REFUTE of ossicular reconstruction as a route to hearing rehabilitation in FEO: middle-ear reconstruction did not improve thresholds where the ossicles were absent.

PMID:15793411 SUPPORT Human Clinical

"Common ossiculoplasty for improving the hearing thresholds in this condition may be unsuccessful; therefore, both surgeons and patients must be completely aware of the contingent undesirable results."

The authors' warning, which is why implantation and amplification rather than ossiculoplasty are the rehabilitation route recorded here.

Dental Surveillance and Prosthodontic Care

Action: dental surveillance and prosthodontic care Ontology label: Supportive Care NCIT:C15747

Surveillance of the permanent dentition for external root resorption from childhood, preservation of teeth where feasible, prosthodontic replacement of lost teeth, and caution with orthodontic force and invasive dental surgery. Root resorption is often the presenting finding in a child and is a prognosticator of later bone disease; the recommendation that unexplained external root resorption should prompt genetic testing is recorded in the diagnosis section. Whether antiresorptive drugs slow root resorption is unproven; alendronate was proposed for that purpose in the allelic ESH family before the gene was known.

Target Phenotypes: External cervical and apical root resorption of permanent teeth HP:0006486

Show evidence (2 references)

PMID:10509339 SUPPORT INDIRECT Human Clinical

"Conventional treatment strategies of root resorption offer only a poor prognosis for the dentition."

The poor dental prognosis with conventional management, from the family later shown to have the allelic 15-bp duplication; indirect for that reason.

PMID:10509339 SUPPORT INDIRECT Human Clinical

"Therapy using alendronate, a bisphosphonate compound and a potent inhibitor of osteoclastic activity, has reduced alkaline phosphatase levels, bone pain, and may offer an effective strategy to prevent tooth root resorption in this group of diseases."

The proposal, not yet tested, that antiresorptive therapy might protect the dentition; indirect for the same reason.

🔬

Biochemical Markers

3

Elevated serum alkaline phosphatase (Variably elevated)

Context: Total or bone-specific alkaline phosphatase is the routine marker of the generalised high turnover and of response to antiresorptive treatment. It is variably raised and can be in the upper normal range in mild or early disease, so a normal value does not exclude the diagnosis.

Show evidence (3 references)

PMID:3346299 SUPPORT Human Clinical

"The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."

The original biochemical profile.

PMID:16831914 SUPPORT Other

"Biochemical markers indicate rapid skeletal remodeling."

Review statement that the markers read out rapid remodelling. Evidence source is OTHER because this is a review.

PMID:36740137 SUPPORT INDIRECT Human Clinical

"Biochemical studies indicated increased bone turnover with elevated urinary N-telopeptide levels and serum alkaline phosphatase in the upper normal range."

Shows that alkaline phosphatase can sit in the upper normal range while resorption markers are raised. Indirect because the patient carried the allelic 12-bp duplication rather than the FEO allele.

Elevated urinary bone resorption markers (Variably elevated)

Context: Urinary hydroxyproline in the original descriptions; urinary N-telopeptide and other collagen crosslink markers in later reports of the allelic disorders. These are the markers used to titrate antiresorptive therapy.

Show evidence (2 references)

PMID:2530018 SUPPORT Human Clinical

"The serum alkaline phosphatase and urinary hydroxyproline are elevated to a variable degree, whereas other biochemical indices are normal."

The resorption marker in the original kindred.

PMID:36740137 SUPPORT INDIRECT Human Clinical

"Biochemical studies indicated increased bone turnover with elevated urinary N-telopeptide levels and serum alkaline phosphatase in the upper normal range."

Urinary N-telopeptide as the modern resorption marker; indirect because the case carries the allelic 12-bp duplication.

Normal serum calcium and phosphate (Normal in untreated FEO)

Context: Calcium, phosphate and the other routine indices are normal in FEO, which is one of the features that separates it from the allelic expansile skeletal hyperphosphatasia, where episodic hypercalcaemia occurs, and from immobilisation hypercalcaemia in the juvenile Paget phenotype. After potent antiresorptive treatment, prolonged hypocalcaemia is the hazard.

Show evidence (2 references)

PMID:3346299 SUPPORT Human Clinical

"The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."

The other biochemical indices, including calcium, are normal.

PMID:11771666 SUPPORT Human Clinical

"Absence of large osteolytic lesions with cortical thinning in major long bones, together with bouts of hypercalcemia, indicated that ESH is not a variant of familial expansile osteolysis (FEO)."

The contrast that defines the boundary: hypercalcaemia belongs to ESH, and its absence in FEO was one of the two features used to separate the disorders.

🔬

Diagnosis

6

Clinical Recognition of the Deafness, Root Resorption and High-Turnover Osteolysis Triad

The diagnosis is suspected from the stereotyped sequence: conductive hearing loss from early childhood, external root resorption and premature loss of the permanent teeth in adolescence, and from the second decade painful expansile osteolytic lesions of the limb bones on a background of raised bone-turnover markers with normal calcium and phosphate. A family history compatible with autosomal dominant transmission strengthens the suspicion but sporadic cases occur, and in a child the presenting finding is usually the deafness or unexplained multiple root resorption at the dental clinic. No consensus diagnostic criteria exist; recognition of the pattern is what prompts the imaging and molecular workup below.

Clinical Evaluation NCIT:C124351

Results: A compatible clinical pattern that triggers biochemical, imaging and TNFRSF11A testing; not by itself diagnostic.

Show evidence (3 references)

PMID:36740137 SUPPORT Human Clinical

"Constitutive activation of RANK signaling should be considered a possible cause in any young person with rapid bone turnover, particularly in the context of early-onset deafness and/or root resorption of permanent teeth."

The authors' diagnostic rule for the whole RANK signal-peptide series, naming the triad of rapid turnover, early deafness and root resorption as the trigger for suspecting the disorder.

PMID:36740137 SUPPORT Human Clinical

"FEO typically presents with childhood-onset deafness followed by resorption of permanent dentition, and then appendicular bone pain, fractures, and deformities from progressive focal expansile osteolytic lesions emerging from a background of generalized high bone turnover."

The clinical sequence on which recognition rests.

PMID:32075714 SUPPORT Human Clinical

"The patient was not diagnosed with FEO until the age of 10 years, when she presented to the dental clinic with advanced ERR in several permanent teeth."

A child born with missing ossicles whose diagnosis was only made when root resorption brought her to the dental clinic, which is why dental presentation is named as a route to recognition.

Skeletal Radiography

Plain radiographs of symptomatic sites, or a skeletal survey, show the two classes of change described in the original kindred: generalised alteration of the trabecular pattern and modelling of the long bones, which can be seen before any focal lesion, and focal lytic areas that enlarge along the shaft, expand the bone and thin the cortex until the medulla is replaced by fibrous and then fatty tissue. The distribution is the discriminating feature: almost all lesions are appendicular, and the pelvis, spine and skull that classic Paget disease favours are spared. Radiographs are also how lesion advance, fracture and response to treatment are followed.

plain radiography of the limb bones NCIT:C38101

Results: Appendicular expansile lytic lesions with medullary expansion and cortical thinning, with or without generalised trabecular coarsening; the axial skeleton is spared. The radiological differential is Paget disease, polyostotic fibrous dysplasia and osteofibrous dysplasia.

Show evidence (6 references)

PMID:2353208 SUPPORT Human Clinical

"Generalised features are either altered trabecular pattern or modelling abnormalities."

The generalised radiographic changes of the original kindred.

PMID:2353208 SUPPORT Human Clinical

"Focal features comprise lytic areas which progressively enlarge, producing expansion of the bone and eventual disintegration due to fibrous and finally fatty replacement of the normal medulla."

The focal radiographic lesion and its evolution.

PMID:2353208 SUPPORT Human Clinical

"Radiologically, the differential diagnosis refers to Paget's disease, polyostotic fibrous dysplasia, and osteofibrous dysplasia."

The radiological differential named by the radiographic series.

+ 3 more references

Technetium-99m Bone Scintigraphy

Whole-body radionuclide bone scan maps the extent of disease: tracer uptake is increased at focal osteolytic lesions and, in the original kindred, in the tibiae of patients who had no focal lesion, reflecting the generalised high turnover. It is the imaging test that shows the multifocal, polyostotic nature of the disease in one study and identifies lesions before they are symptomatic. A normal scan does not exclude a signal-peptide duplication: a child with the allelic 12-bp duplication and mild disease had a normal scan despite raised resorption markers.

whole-body technetium-99m bone scintigraphy NCIT:C17646

Results: Increased tracer uptake at multiple appendicular foci, sometimes with diffusely increased uptake in the tibiae without a focal lesion; may be normal in early or mild disease.

Show evidence (5 references)

PMID:30756140 SUPPORT Other

"Radionuclide bone scans show increased tracer uptake at the site of focal osteolytic lesions."

The scintigraphic finding at focal lesions. Evidence source is OTHER because this is a review.

PMID:30756140 SUPPORT Other

"In addition, tracer uptake was reported to be increased in the tibiae of patients without focal bone lesions in keeping a generalized elevation in bone turnover."

Increased uptake without a focal lesion, which is the scintigraphic readout of the generalised remodelling. Evidence source is OTHER because this is a review.

PMID:15793411 SUPPORT Human Clinical

"There was an increase in uptake and activity at multiple foci of the whole skeleton."

Whole-body Tc-99m MDP scans in three affected family members showing multifocal increased uptake.

+ 2 more references

Panoramic Dental Radiography and Cone-Beam CT for Root Resorption

Clinical and radiographic dental examination detects cervical and apical external root resorption of the permanent teeth, which is an early manifestation, precedes skeletal disease in many patients and predicts later bone involvement. A panoramic radiograph is the screening view; cone-beam CT resolves the extent of resorption of individual roots and is the modality on which progression has been followed. Multiple external root resorption with no local cause in a child should prompt the systemic and genetic evaluation recorded below. Cone-beam CT is carried in the preferred term because the schema binds one procedure term per diagnostic item; NCIT:C71695 is its identifier.

panoramic dental radiography and cone-beam CT NCIT:C150663

Results: Cervical and/or apical external root resorption of several permanent teeth, with narrowed pulp chambers from irregular secondary dentine; deciduous teeth largely spared.

Show evidence (4 references)

PMID:2216357 SUPPORT Human Clinical

"Twenty-seven family members, aged 3 to 60 years, were examined clinically and radiographically, and it was found that cervical and/or apical root resorption is an early manifestation of the dysplasia."

The dental radiographic study of the original kindred, which established root resorption as an early, radiographically detectable manifestation.

PMID:2216357 SUPPORT Human Clinical

"Root resorption may therefore be a good prognosticator for later bone involvement."

Why a dental finding belongs in the diagnostic workup: it predicts the skeletal disease.

PMID:36740137 SUPPORT INDIRECT Human Clinical

"Panoramic dental radiographs had disclosed root resorption of the permanent maxillary and mandibular central incisors with ongoing concerns for early loss of her permanent teeth"

The panoramic radiograph as the view that disclosed the resorption; indirect because the child carried the allelic 12-bp duplication.

+ 1 more reference

Temporal-Bone CT and MRI with Audiometry

Audiometry and tympanometry characterise the hearing loss, which is conductive at first and later mixed, and coronal high-resolution CT of the temporal bones shows the state of the ossicular chain, from hypoplastic and dysmorphic ossicles to their complete absence. MRI adds the inner ear and soft tissue. The imaging matters for management as well as diagnosis: where the ossicles are absent, ossicular reconstruction has not improved thresholds, so the finding steers rehabilitation toward amplification or implantation rather than ossiculoplasty.

high-resolution temporal-bone CT with MRI and audiometry NCIT:C17204

Results: Conductive or mixed hearing loss with a type AD tympanogram and absent acoustic reflexes; hypoplastic, dysmorphic or absent middle-ear ossicles on temporal-bone CT.

Show evidence (4 references)

PMID:15793411 SUPPORT Human Clinical

"The temporal-bone computed-tomography scan in the coronal view of all three patients and also exploratory middle-ear surgery, which was done on two of the patients, showed no ossicles in the middle ear of either ear in all three cases."

Coronal temporal-bone CT demonstrating the ossicular lesion, confirmed at surgery.

PMID:15793411 SUPPORT Human Clinical

"Audiometry indicated mild to moderate conductive and mixed hearing loss and also an AD-type tympanogram pattern along with an absence of acoustic reflexes in both ears of the cases."

The audiometric and tympanometric profile.

PMID:36740137 SUPPORT INDIRECT Human Clinical

"High resolution computed tomography (CT) and magnetic resonance imaging (MRI) of the temporal bones showed the handle of the malleus was present bilaterally"

CT and MRI of the temporal bones used to define the ossicular abnormality; indirect because the child carried the allelic 12-bp duplication.

+ 1 more reference

TNFRSF11A Exon 1 Duplication Testing

Molecular confirmation is a heterozygous in-frame 18-bp tandem duplication in exon 1 of TNFRSF11A, found in every FEO kindred published. Because the lesion is a small tandem duplication in a GC-rich repeated sequence, the assay must be duplication-sensitive: Sanger sequencing of exon 1 in both directions, or a skeletal-dysplasia panel that provides deletion/duplication analysis alongside sequencing, detects it; a pipeline that does not resolve small tandem duplications can miss it. The length of the duplication identifies the allelic disorder (27 bp for early-onset familial Paget disease, 15 bp for expansile skeletal hyperphosphatasia, 12 bp for panostotic expansile bone disease), so the test also settles the differential among the RANK signal-peptide disorders. Parental testing distinguishes inherited from de novo duplications, and cascade testing identifies at-risk relatives before skeletal lesions form. Unexplained multiple external root resorption in a child is a recognised trigger for testing.

duplication-sensitive sequencing of TNFRSF11A exon 1 NCIT:C15709

Results: Heterozygous 84dup18, or the one-base-shifted 18-bp duplication, in exon 1 of TNFRSF11A.

Show evidence (6 references)

PMID:10615125 SUPPORT Human Clinical

"We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB)."

The discovery study locating the diagnostic lesion in exon 1.

PMID:12568416 SUPPORT Human Clinical

"Identical insertional mutations in the first exon of RANK have been identified in all published FEO kindreds."

The recurrence of the same lesion across kindreds is what makes exon 1 testing a confirmatory test rather than a research finding.

PMID:36740137 SUPPORT Human Clinical

"An 18-bp duplication in TNFRSF11A has been reported in all kindreds with FEO, whereas a 12-bp duplication was found in the young man with PEBD complicated by a massive jaw tumor."

Duplication length as the discriminator among the allelic disorders.

+ 3 more references

📈

Progression

3

Early-onset hearing loss

Age: Childhood, sometimes as early as 4 years of age

Hearing loss is the earliest clinical manifestation, from resorption of the middle-ear ossicles, and precedes the skeletal lesions by years.

Show evidence (1 reference)

PMID:2353208 SUPPORT Human Clinical

"Clinically, hearing loss is the earliest manifestation of the disease, presenting sometimes as early as 4 years of age."

The radiographic series of the original kindred places hearing loss first in the clinical sequence and gives the earliest recorded age.

External root resorption and premature tooth loss

Age: Childhood onward

Apical and cervical root resorption of the permanent teeth is the usual presenting finding in a child and leads to premature tooth loss. The cached abstract gives no age of onset for the dental phase; the paediatric case in the diagnosis section documents root resorption as the presenting finding.

Show evidence (1 reference)

PMID:2353208 SUPPORT Human Clinical

"Apical and cervical resorption of teeth is extremely common, resulting in premature loss of teeth."

The same series records the dental phase and its outcome of premature tooth loss.

Progressive focal expansile osteolysis of the appendicular skeleton

Age: Early adulthood onward

Focal lytic lesions, most of them in the long bones, develop usually in early adulthood and enlarge progressively, expanding the bone and ending in fibrous and then fatty replacement of the medulla. The rates of lesion advance and the fracture counts reported in the full text of the radiographic series are not in the cached abstract and are not curated.

Show evidence (3 references)

PMID:10615125 SUPPORT Human Clinical

"The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity."

Places the onset of the focal osteolytic lesions in early adulthood and in the long bones.

PMID:2353208 SUPPORT Human Clinical

"Focal features comprise lytic areas which progressively enlarge, producing expansion of the bone and eventual disintegration due to fibrous and finally fatty replacement of the normal medulla."

The progressive course of an individual lesion from lytic focus to expansion and medullary replacement.

PMID:2353208 SUPPORT Human Clinical

"Almost 90% of these lesions occur in the appendicular skeleton."

The appendicular predominance of the focal lesions.

📊

Prevalence

1

Worldwide, reported kindreds and cases

Cases In Literature Ultra Rare

No population estimate exists. In 2006 the disease had been observed world-wide in only three kinships and two unrelated American individuals; since then families or cases have been added from Spain, Iran, the Czech Republic, Australia and elsewhere, and the 2023 literature describes the TNFRSF11A duplication disorders collectively as ultra-rare. The Northern Irish kindred alone accounts for over 40 affected members across five generations.

Show evidence (4 references)

PMID:16470392 SUPPORT Human Clinical

"Familial expansile osteolysis (FEO, MIM174810) is a rare syndrome which was observed world-wide in only three kinships and in two unrelated American individuals."

The 2006 world count of known kindreds and cases.

PMID:17447113 SUPPORT Human Clinical

"An 18-bp duplication in the first exon of the TNFRSF11A gene encoding RANK has been previously identified in four FEO pedigrees."

Four molecularly confirmed pedigrees by 2007, before the Iranian family was added.

PMID:36740137 SUPPORT Human Clinical

"Ultra-rare mendelian osteolytic disorders caused by different length in-frame activating duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) comprise familial expansile osteolysis (FEO), expansile skeletal hyperphosphatasia (ESH), early-onset..."

The ultra-rare designation for the whole allelic series.

+ 1 more reference

🐁

Animal Models

2

Tnfrsf11a 75dup27 heterozygous knock-in mouse

A knock-in mouse carrying the human 27-bp signal-peptide duplication that causes early-onset familial Paget disease of bone, the allelic disorder of FEO. Heterozygotes develop age-dependent focal osteolytic lesions of the hind limbs, and zoledronic acid prevents them. Marrow cells show impaired RANKL-induced osteoclast formation and signalling but increased osteoclast survival independent of RANKL. It is the only knock-in model of a TNFRSF11A signal-peptide duplication; no mouse carrying the FEO 18-bp allele has been reported.

Species

Mouse

Genotype

Tnfrsf11a 75dup27 heterozygous (Tnfrsf11a75dup27/-)

Publication

PMID:33724536

Pathograph links

Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning partially recapitulates fidelity: moderate observes: tissue Reproduces age-dependent focal osteolytic lesions of the limb bones from a heterozygous signal-peptide duplication, which is the defining lesion of this node.

Limitations: The allele is the PDB2 27-bp duplication, not the FEO 18-bp one, so the model speaks to the shared signal-peptide mechanism rather than to FEO specifically; the human 27-bp phenotype is Paget-like with lytic-sclerotic lesions and jaw involvement rather than purely lytic, expansile limb disease. The lesions appear with age in a mouse, not from the second decade of a human life, and the abstract reports no hearing or dental phenotype.

Divergences from the human mechanism

species mismatch qualifying

Murine long bones and remodelling rates differ from human, and the mouse does not report the deafness and dental disease that precede skeletal disease in patients.

Readouts

Focal osteolytic lesions of the hind limbs

Direction: INCREASED

Interpretation: Age-dependent focal osteolysis in heterozygotes is the tissue-level correlate of the human lesion in this model.

Show evidence (1 reference)

PMID:33724536 SUPPORT Model Organism

"This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling."

Reports the focal osteolytic lesions that constitute this readout.

Lesion development under zoledronic acid

Direction: ABOLISHED

Interpretation: Complete prevention of lesions by an osteoclast-targeted drug shows that the lesion is osteoclast-driven and drug-preventable in this model.

Show evidence (1 reference)

PMID:33724536 SUPPORT Model Organism

"Treatment of these mice with zoledronic acid completely prevented the development of lesions."

The prevention result behind this readout.

Show evidence (1 reference)

PMID:33724536 SUPPORT Model Organism

"Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein."

The authors' own framing of the model as informative for the whole family of signal-peptide duplication disorders, FEO included.

Constitutive Osteoclast Formation, Survival and Activation partially recapitulates fidelity: moderate observes: cellular Shows the heterozygous osteoclast phenotype: RANKL-driven formation is impaired, yet survival is prolonged without RANKL and lesions form in vivo, which is the paradox this node carries.

Limitations: Same allelic caveat as above. In addition, the model shows impaired rather than enhanced RANKL-induced osteoclast formation in marrow culture, so it recapitulates the survival component of the node and the in vivo outcome but not the increased differentiation the module target asserts.

Divergences from the human mechanism

species mismatch qualifying

Mouse marrow osteoclastogenesis assays are a proxy for the human osteoclast lineage; no patient osteoclast data exist for comparison.

Readouts

Osteoclast survival in the absence of RANKL

Direction: INCREASED

Interpretation: Prolonged osteoclast survival independent of ligand is the cellular signature of the mutant allele in this model.

Show evidence (1 reference)

PMID:33724536 SUPPORT Model Organism

"Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a75dup27/- animals, but that osteoclast survival was increased independent of RANKL stimulation."

Reports both the impaired formation recorded in the limitations and the increased survival that is this readout.

Show evidence (1 reference)

PMID:33724536 SUPPORT Model Organism

"This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling."

Supports treating the heterozygous model as informative for the osteoclast node.

Tnfrsf11a 75dup27 homozygous knock-in mouse

The same allele in homozygous form. Rather than a more severe osteolytic disease, homozygotes have osteopetrosis at birth with complete absence of osteoclasts, and their marrow cells fail to form osteoclasts in response to RANKL and M-CSF. The result is curated because it is the single most informative negative finding about the mechanism: a receptor that was simply constitutively active would not abolish osteoclasts when present in two copies.

Species

Mouse

Genotype

Tnfrsf11a 75dup27 homozygous (Tnfrsf11a75dup27/75dup27)

Publication

PMID:33724536

Pathograph links

Constitutive Osteoclast Formation, Survival and Activation fails to recapitulate fidelity: low observes: cellular Two copies of the mutant allele produce the opposite of the human disease at the osteoclast: no osteoclasts at all.

Limitations: No homozygous human exists, so the model tests a state the disease never occupies; its value is mechanistic, not phenotypic. It shows that the mutant receptor alone cannot drive osteoclastogenesis and that the human heterozygous phenotype depends on the co-presence of wild-type RANK, which is the content of the knowledge gap.

Show evidence (2 references)

PMID:33724536 SUPPORT Model Organism

"Surprisingly, Tnfrsf11a75dup27/75dup27 homozygotes had osteopetrosis at birth, with complete absence of osteoclasts."

The homozygous osteopetrosis that is the failure to recapitulate.

+ 1 more reference

{ }

Source YAML

click to show

name: Familial Expansile Osteolysis
creation_date: "2026-09-04T23:23:40Z"
description: >-
  Familial expansile osteolysis (FEO) is an ultra-rare autosomal dominant
  disorder of osteoclast regulation in which a heterozygous in-frame tandem
  duplication in exon 1 of TNFRSF11A lengthens the signal peptide of RANK, the
  receptor that drives osteoclast formation. The mutant receptor is not
  processed normally: its signal peptide is not cleaved, most of the protein
  is retained in the endoplasmic reticulum, and osteoclast lineage cells that
  carry one copy of it form more osteoclasts, keep them alive longer and
  resorb more bone than RANK ligand alone would instruct. The result is a
  skeleton in which remodelling runs fast everywhere and, at scattered sites
  in the limb bones, runs away entirely.

  The clinical sequence is stereotyped and is the basis of recognition. The
  first sign is usually hearing loss in early childhood, conductive at first
  and later mixed, reflecting resorption and in some patients complete loss of
  the middle-ear ossicles. The permanent teeth then undergo idiopathic
  external root resorption and are lost prematurely in adolescence. From the
  second decade, focal osteolytic lesions appear in the long bones of the
  limbs, particularly the tibia, and advance along the shaft, thinning the
  cortex and expanding the medullary cavity until the bone is deformed,
  painful and liable to pathological fracture. Serum alkaline phosphatase and
  urinary hydroxyproline are variably raised, and the end stage of a lesion is
  fat-filled bone rather than the sclerosis of Paget disease.

  What organises this entry is the unresolved question of how a misprocessed
  receptor produces overactive osteoclasts. The original discovery study found
  that the mutant proteins increased NF-kappaB signalling in vitro and
  treated them as activating mutations; a later study showed that this
  constitutive activation appears only with overexpression, that mutant RANK
  cannot be activated by its ligand, and that the phenotype must arise from
  something the mutant allele does to signalling in heterozygous cells. The
  chain below records the demonstrated steps, marks the inferred one, and
  carries the disagreement as a knowledge gap rather than settling it.
category: Mendelian
disease_term:
  preferred_term: Familial Expansile Osteolysis
  term:
    id: MONDO:0008275
    label: familial expansile osteolysis
synonyms:
- FEO
- McCabe disease
- Hereditary expansile polyostotic osteolytic dysplasia
- HEPOD
- Expansile osteolysis, familial
- Osteolysis, familial expansile
parents:
- Osteolysis Syndromes
- Metabolic Bone Disorders
- Mendelian Disorders of RANKL/OPG/RANK Signalling
notes: >-
  Scope and lump/split decision. This entry is the 18-bp duplication disorder
  (84dup18 and the one-base-shifted equivalent) that carries the name familial
  expansile osteolysis and MONDO:0008275. The allelic TNFRSF11A signal-peptide
  disorders are described here but are not curated as subtypes: early-onset
  familial Paget disease of bone (PDB2, MONDO:0011183; 27-bp duplications
  75dup27, 77dup27, 78dup27, 72dup27), expansile skeletal hyperphosphatasia
  (ESH; 15-bp duplication 84dup15; no MONDO term was found), juvenile Paget
  disease 2 (87dup15) and panostotic expansile bone disease (PEBD; 12-bp
  duplication). They share the molecular lesion, the deafness and the tooth
  loss, and differ in the skeletal pattern: ESH has hyperostotic widening of
  the long bones with painful phalangeal lesions and episodic hypercalcaemia
  rather than large cortical-thinning osteolytic lesions; PDB2 has a Paget-like
  lytic-sclerotic picture with striking jaw and skull involvement; PEBD has
  panostotic disease with massive jaw tumours. Evidence from these allelic
  disorders is used here only where it bears on the shared mechanism or on the
  treatment class, and is marked directness INDIRECT when it does. Juvenile
  Paget disease (TNFRSF11B, osteoprotegerin loss) and classic Paget disease of
  bone (SQSTM1 and others; see Paget_Disease_of_Bone) are different genes and
  different entries; both are cross-referenced because the middle of the
  causal chain, unrestrained RANK signalling into osteoclasts, is common to all
  of them.

  Module conformance. Two nodes conform to osteoporosis_bone_resorption. The
  osteoclast node conforms to RANKL-Driven Osteoclastogenesis with the
  disorder-specific substitution that the module's driver, a raised RANKL/OPG
  ratio, is replaced here by a constitutively mis-signalling RANK receptor;
  the ligand is not in excess, the receptor is out of ligand control. The focal
  osteolysis node conforms to Increased Osteoclastic Bone Resorption. The
  entry deliberately does not conform to the module's Impaired Osteoblastic
  Bone Formation node, because FEO is a high-turnover disease in which
  osteoblast activity is increased alongside osteoclast activity rather than
  deficient; the bone is lost because resorption outruns a formation arm that
  is itself working hard, not because formation has failed.

  Animal model. No mouse carrying the FEO 18-bp duplication has been reported.
  The only knock-in model of a TNFRSF11A signal-peptide duplication carries the
  PDB2 allele 75dup27, and it is curated as a partial model with that caveat.
  Earlier whole-animal work referred to in reviews is not curated because the
  primary reports with quotable methods were not found.

  Provenance. Built from an Edison (Falcon) deep-research report,
  research/Familial_Expansile_Osteolysis-deep-research-falcon.md, which
  passed the Named-Entity-Confusion preflight against MONDO:0008275. Falcon
  cites by DOI and by corpus key; every source used here was resolved to its
  PubMed record and quoted from the cached abstract, and the primary papers
  the report did not carry (the 1988 and 1989 Northern Irish descriptions,
  the 1990 dental studies, the 1994 linkage paper, the 2003 and 2007
  mutation papers, the 2005 ossicle study and the 2025 denosumab case) were
  found through PubMed directly. Three papers the brief asked for, the 2002
  American kindred description in Medicine, the 2002 Spanish kindred paper and
  the 1996 incus necrosis study, have no abstract in PubMed and are listed as
  references without quoted evidence. The Schafer 2014 paper named in the
  brief as a denosumab report is the panostotic expansile bone disease case
  and describes alendronate and pamidronate, not denosumab; it is cited for
  what it says. No GeneReviews chapter exists for this disorder.
references:
- reference: PMID:10615125
  title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
- reference: PMID:21472776
  title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
- reference: PMID:30756140
  title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
- reference: PMID:3346299
  title: "Familial expansile osteolysis. A new dysplasia."
- reference: PMID:11889411
  title: "Familial expansile osteolysis (excessive RANK effect) in a 5-generation American kindred."
- reference: PMID:12362049
  title: "Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene."
- reference: PMID:8643278
  title: "Conductive hearing loss caused by hereditary incus necrosis: a study of familial expansile osteolysis."
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  expressivity: VARIABLE
  description: >-
    Transmitted as an autosomal dominant trait through five generations of the
    original Northern Irish kindred and in every family reported since. The
    heterozygous duplication is highly penetrant, but expression varies
    markedly between and within families carrying the identical allele: some
    relatives have deafness and tooth loss with few or no osteolytic lesions,
    others have extensive limb and even skull disease from childhood. Sporadic
    cases with no family history occur. Penetrance is recorded as complete on
    the strength of the kindred descriptions; no formal penetrance estimate
    has been published.
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 40 cases in one family of an autosomal dominant bone dysplasia, which, though similar in some aspects to Paget's disease, seems unique in some features and in its natural history."
    explanation: >-
      The original description of the Northern Irish kindred establishes the
      autosomal dominant pattern from 40 affected members of one family.
  - reference: PMID:7911698
    reference_title: "Genetic linkage of familial expansile osteolysis to chromosome 18q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial expansile osteolysis is a rare bone dysplasia which is transmitted as an autosomal dominant trait in a large kindred in Northern Ireland."
    explanation: >-
      The linkage study restates the dominant transmission on which the
      18q mapping depended.
  - reference: PMID:17447113
    reference_title: "Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite having the identical mutation, phenotypic variations among affected individuals of the same and different pedigrees were noted."
    explanation: >-
      Supports variable expressivity: the same 18-bp duplication produces
      different phenotypes within and between pedigrees.
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One had no family history of FEO, but presented with bilateral hearing loss at an early age, deterioration of teeth, and severe pain and swelling in the distal tibia before the age of 20."
    explanation: >-
      Documents a sporadic case without family history, so the dominant
      pattern includes new occurrences and not only inherited ones.
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: >-
      Harrison's covers Paget disease and the related high-turnover bone
      dysplasias in the metabolic bone disease chapters of the endocrinology
      and metabolism Part.
    evidence:
    - reference: PMID:30756140
      reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Insertion mutations within exon 1 of the TNFRSF11A gene, encoding the receptor activator of nuclear factor kappa B (RANK), cause severe PDB-like disorders including familial expansile osteolysis, early-onset familial PDB and expansile skeletal hyperphosphatasia."
      explanation: >-
        A review of the rare inherited Paget-like disorders places FEO among
        the PDB-like metabolic bone diseases.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian skeletal dysplasia with a single causal gene.
    evidence:
    - reference: PMID:10615125
      reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling."
      explanation: >-
        Frames the disorder as a rare autosomal dominant Mendelian disease.
  isds_skeletal_category:
  - classification_value: osteolysis
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et
      al., PMID:36779427), group "Osteolysis group"; listed as familial
      expansile osteolysis, TNFRSF11A. The placement is a taxonomy mapping,
      not an empirical claim, and the nosology abstract carries no
      per-disorder sentence to quote.
pathophysiology:
- name: TNFRSF11A Exon 1 Signal-Peptide Tandem Duplication
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The initiating lesion. A heterozygous in-frame 18-base-pair tandem
    duplication in exon 1 of TNFRSF11A, the gene encoding receptor activator
    of NF-kappaB (RANK), inserts six amino acids into the signal peptide of
    the receptor. The classic allele is 84dup18; a second 18-bp duplication
    one base proximal to it adds the same six residues. Intragenic haplotypes
    show that the identical duplication has arisen independently at least
    three times, and the exon 1 sequence can form a stable secondary
    structure that may favour tandem duplication, which is why the same
    lesion recurs in unrelated families. The allelic 27-, 15- and 12-bp
    duplications in the same signal peptide cause the related disorders
    described in the notes.
  genes:
  - preferred_term: TNFRSF11A
    term:
      id: hgnc:11908
      label: TNFRSF11A
  genetic_context:
    genes:
    - preferred_term: TNFRSF11A
      term:
        id: hgnc:11908
        label: TNFRSF11A
    allele_type: in-frame 18-bp tandem duplication in exon 1 (signal peptide)
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Classified as gain of function on the basis of the original functional
      characterisation, in which both signal-peptide duplications increased
      RANK-mediated NF-kappaB signalling in vitro, and on the heterozygous
      disease phenotype of excessive osteoclast activity. The category is held
      with the caveat recorded in the knowledge gap below: the mutant
      receptor by itself cannot be activated by ligand, and how one mutant
      allele overactivates osteoclasts in heterozygous cells is unresolved.
  evidence:
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB)."
    explanation: >-
      The discovery of the causal lesion: heterozygous exon 1 insertions in
      affected members of four families.
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule."
    explanation: >-
      Identifies the 18-bp duplication as the FEO allele and locates both
      duplications in the signal peptide.
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutational analysis of the TNFRSF11A gene in our patients demonstrated an 18 base pair tandem duplication, one base proximal to the duplications previously reported."
    explanation: >-
      The second 18-bp allele, shifted by one base, in two unrelated
      patients.
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This novel mutation results in addition of the same six amino acids to the RANK signal peptide that has been observed previously."
    explanation: >-
      Both 18-bp alleles produce the same six-residue extension of the
      signal peptide, which is why they are one disorder.
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further analysis of the exon 1 sequence demonstrated that it has the ability to form a stable secondary structure that may facilitate the generation of tandem duplications."
    explanation: >-
      Offers a reason for the recurrence of the same duplication in
      unrelated families.
  - reference: PMID:17447113
    reference_title: "Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although the mutation in the Iranian and four of the previously described FEO pedigrees was the same, haplotypes based on the intragenic SNPs suggest that the mutations do not share a common descent."
    explanation: >-
      Haplotype evidence that the recurrent 18-bp duplication arose
      independently rather than from a founder.
  - reference: PMID:7911698
    reference_title: "Genetic linkage of familial expansile osteolysis to chromosome 18q."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gene which causes the disease shows tight linkage with several polymorphic markers on chromosome 18q with a maximum lod score of 11.53 at a recombination fraction of 0.00 with D18S64."
    explanation: >-
      The linkage result that placed the disease at 18q, where TNFRSF11A
      maps, before the gene was identified.
  downstream:
  - target: Failure of RANK Signal-Peptide Cleavage and Endoplasmic Reticulum Retention
    causal_link_type: DIRECT
    description: >-
      Lengthening the signal peptide prevents its cleavage, so the
      receptor is not processed through the secretory pathway normally.
    evidence:
    - reference: PMID:10615125
      reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide."
      explanation: >-
        The first demonstration that the duplication abolishes normal
        signal-peptide cleavage, which is the step this edge asserts.
- name: Failure of RANK Signal-Peptide Cleavage and Endoplasmic Reticulum Retention
  biological_scale: MOLECULAR
  description: >-
    The elongated signal peptide is not removed. In two independent in vitro
    translation systems the mutant proteins fail signal-peptide cleavage,
    and when expressed in cells mutant RANK does not reach the plasma
    membrane but accumulates in extensive areas of organised smooth
    endoplasmic reticulum, where wild-type RANK is found at the membrane and
    in the Golgi. Reviews describe the consequence as the protein translated
    from the mutant allele being trapped in the endoplasmic reticulum. The
    mutant receptor that does accumulate cannot be activated by RANK ligand,
    so whatever it does to the cell, it does not do it by responding to
    ligand in the ordinary way.
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  biological_processes:
  - preferred_term: retention of mutant RANK in the endoplasmic reticulum
    term:
      id: GO:0035437
      label: maintenance of protein localization in endoplasmic reticulum
    modifier: INCREASED
  evidence:
  - reference: PMID:21472776
    reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This intracellular accumulation of the mutant proteins is probably the result of lack of signal peptide cleavage because, using two in vitro translation systems, we demonstrate that the mutations in RANK prevent cleavage of the signal peptide."
    explanation: >-
      Direct demonstration that the duplications prevent signal-peptide
      cleavage, and the authors' link from that failure to intracellular
      accumulation.
  - reference: PMID:21472776
    reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When overexpressed, mutant RANK did not localize to the plasma membrane but localized to extensive areas of organized smooth endoplasmic reticulum, whereas, as expected, wild-type RANK was detected at the plasma membrane and in the Golgi apparatus."
    explanation: >-
      The localisation result behind the endoplasmic-reticulum retention in
      this node's name.
  - reference: PMID:21472776
    reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Importantly, only cells expressing wild-type RANK demonstrated ligand-dependent activation of NF-κB."
    explanation: >-
      The retained mutant receptor is not ligand-responsive, which
      constrains every downstream explanation of the disease.
  - reference: PMID:20458572
    reference_title: "New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These prevent signal peptide cleavage, trapping the protein translated from the mutated allele in the endoplasmic reticulum."
    explanation: >-
      Review summary of the cleavage failure and ER trapping. Evidence source
      is OTHER because this is a review.
  downstream:
  - target: Ligand-Independent RANK Signalling and NF-kappaB Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The step that is inferred rather than demonstrated. The retained,
      ligand-unresponsive mutant receptor is nonetheless associated with
      increased NF-kappaB signalling in the discovery study and with
      overactive osteoclasts in patients; the route, whether self-association
      of misfolded receptor, an unfolded-protein response, or an effect of the
      mutant allele on the wild-type receptor in the same cell, is
      unresolved.
- name: Ligand-Independent RANK Signalling and NF-kappaB Activation
  biological_scale: MOLECULAR
  description: >-
    RANK signalling that is no longer under the control of RANK ligand. In
    the discovery study, recombinant mutant RANK increased RANK-mediated
    NF-kappaB signalling in vitro relative to wild type, and the mutations
    were read as activating; reviews state the mechanism as osteoclast
    activation through NF-kappaB independent of ligand. The later study of
    stably transfected cells found that constitutive activation occurred only
    with overexpression, of wild-type as well as mutant RANK, and not at low
    expression levels, and concluded that the disease cannot be explained by
    the mutant receptor alone. The modifier is recorded as GAIN_OF_FUNCTION
    rather than INCREASED because the claim is qualitative: the pathway has
    escaped its ligand, not merely risen above its normal level. The
    disagreement about how it escaped is the entry's knowledge gap.
  biological_processes:
  - preferred_term: ligand-independent RANK-mediated NF-kappaB signalling
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: GAIN_OF_FUNCTION
  - preferred_term: tumour necrosis factor receptor superfamily (RANK) signalling
    term:
      id: GO:0033209
      label: tumor necrosis factor-mediated signaling pathway
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation."
    explanation: >-
      The original activating-mutation interpretation on which the gain of
      function classification rests.
  - reference: PMID:30756140
    reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mutations interfere with normal processing of RANK and cause osteoclast activation through activation of nuclear factor kappa B (NFκB) independent of RANK ligand stimulation."
    explanation: >-
      A review states the ligand-independent NF-kappaB activation that names
      this node. Evidence source is OTHER because this is a review.
  - reference: PMID:21472776
    reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "We show here that constitutive activation of NF-κB occurred in HEK293 cells overexpressing wild-type or mutant RANK but not in stably transfected cell lines expressing low levels of each RANK gene."
    explanation: >-
      Recorded as REFUTE of the simple constitutive-activation model: at
      physiological expression levels the mutant receptor did not activate
      NF-kappaB, and overexpression activated it regardless of mutation.
  - reference: PMID:21472776
    reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Previous studies have shown that overexpression of these mutant proteins causes constitutive activation of NF-κB signaling in vitro, and it has been assumed that this accounts for the focal osteolytic lesions that are seen in vivo."
    explanation: >-
      States the assumption the field had made, and that this study set out
      to test, which is the position this node records.
  downstream:
  - target: Constitutive Osteoclast Formation, Survival and Activation
    causal_link_type: DIRECT
    description: >-
      RANK signalling into NF-kappaB is the pathway that instructs osteoclast
      differentiation, survival and activity, so signalling that has escaped
      ligand control produces osteoclasts that are not under the skeleton's
      normal regulation.
    evidence:
    - reference: PMID:21472776
      reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Familial expansile osteolysis and related disorders are caused by heterozygous tandem duplication mutations in the signal peptide region of the gene encoding receptor activator of NF-κB (RANK), a receptor critical for osteoclast formation and function."
      explanation: >-
        Names RANK as the receptor critical for osteoclast formation and
        function, which is why altered RANK signalling lands on the osteoclast.
- name: Constitutive Osteoclast Formation, Survival and Activation
  biological_scale: CELLULAR
  conforms_to: "osteoporosis_bone_resorption#RANKL-Driven Osteoclastogenesis"
  description: >-
    Osteoclasts form, persist and resorb in excess of what the skeleton has
    asked for. Affected bone shows increased osteoclast and osteoblast
    activity, and the mouse carrying the allelic 75dup27 duplication shows
    what the heterozygous state does to the lineage: RANKL-induced osteoclast
    formation and signalling in marrow cells is impaired, yet osteoclast
    survival is increased independently of RANKL, and the animals develop
    focal osteolytic lesions. The same allele in homozygous form abolishes
    osteoclasts altogether and causes osteopetrosis, which shows that the
    mutant receptor is not simply hyperactive but that one mutant allele
    beside a wild-type one changes osteoclast behaviour in a way that neither
    allele alone explains. This node conforms to the module's RANKL-driven
    osteoclastogenesis step with the substitution that the driver is a
    receptor escaped from ligand control rather than an excess of ligand.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: osteoclast differentiation
    term:
      id: GO:0030316
      label: osteoclast differentiation
    modifier: INCREASED
  - preferred_term: osteoclast survival (reduced apoptosis)
    term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity."
    explanation: >-
      The histological observation in patients that both osteoclast and
      osteoblast activity are increased in lesions, which is why this is a
      high-turnover rather than a formation-deficient disease.
  - reference: PMID:33724536
    reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling."
    explanation: >-
      The clearest cellular statement of what a heterozygous signal-peptide
      duplication does to osteoclasts: it extends their survival without
      RANKL. Indirect because the allele is the PDB2 27-bp duplication, not
      the FEO 18-bp one.
  - reference: PMID:33724536
    reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation."
    explanation: >-
      The homozygous result that rules out a simple hyperactive receptor and
      makes the heterozygous interaction the object of the mechanism.
  - reference: PMID:30756140
    reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mutations interfere with normal processing of RANK and cause osteoclast activation through activation of nuclear factor kappa B (NFκB) independent of RANK ligand stimulation."
    explanation: >-
      Review statement of osteoclast activation as the cellular consequence.
      Evidence source is OTHER because this is a review.
  downstream:
  - target: Generalized Accelerated Bone Remodelling
    causal_link_type: DIRECT
    description: >-
      Excess osteoclast activity throughout the skeleton, with coupled
      osteoblast activity, raises the rate of bone remodelling everywhere.
    evidence:
    - reference: PMID:16831914
      reference_title: "Paget's disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signaling."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Biochemical markers indicate rapid skeletal remodeling."
      explanation: >-
        The systemic consequence of the osteoclast lesion, read off the
        turnover markers. Evidence source is OTHER because this is a review.
- name: Generalized Accelerated Bone Remodelling
  biological_scale: TISSUE
  description: >-
    Bone turnover runs fast across the whole skeleton, not only at the focal
    lesions. Bone scintigraphy shows increased uptake at multiple foci, serum
    alkaline phosphatase and urinary hydroxyproline are variably elevated
    while other biochemical indices stay normal, and the skeleton as a whole
    is osteopenic. The focal osteolytic lesions of the limbs, the ossicular
    resorption of the middle ear and the external root resorption of the
    teeth are three site-specific expressions of this generalised state.
  biological_processes:
  - preferred_term: bone remodeling
    term:
      id: GO:0046849
      label: bone remodeling
    modifier: INCREASED
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease shows both general and focal skeletal changes, the latter being mainly in the limbs with an onset from the second decade."
    explanation: >-
      The original description separates the generalised skeletal change
      from the focal limb lesions, which is the distinction this node and the
      next one make.
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."
    explanation: >-
      The turnover markers that read out the generalised remodelling.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was an increase in uptake and activity at multiple foci of the whole skeleton."
    explanation: >-
      Whole-body scintigraphy showing multifocal increased activity, the
      imaging correlate of generalised remodelling.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FEO typically presents with childhood-onset deafness followed by resorption of permanent dentition, and then appendicular bone pain, fractures, and deformities from progressive focal expansile osteolytic lesions emerging from a background of generalized high bone turnover."
    explanation: >-
      States that the focal lesions emerge from a background of generalised
      high turnover, which is the relation between this node and the three
      downstream ones.
  downstream:
  - target: Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning
    causal_link_type: DIRECT
    description: >-
      At scattered sites in the long bones, resorption escapes even the
      accelerated coupling and produces an advancing lytic lesion.
  - target: Middle-Ear Ossicular Resorption
    causal_link_type: DIRECT
    description: >-
      The auditory ossicles are small bones subject to the same osteoclast
      overactivity, and are resorbed early.
  - target: External Root Resorption of Permanent Teeth
    causal_link_type: DIRECT
    description: >-
      Osteoclast-lineage odontoclasts resorb the cervical and apical root of
      the permanent teeth.
  - target: Elevated serum alkaline phosphatase
    causal_link_type: DIRECT
    description: >-
      The osteoblastic arm of accelerated remodelling releases alkaline
      phosphatase into serum.
  - target: Generalized osteopenia
    causal_link_type: DIRECT
    description: >-
      Net loss of bone across the skeleton from remodelling that resorbs
      faster than it refills.
- name: Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning
  biological_scale: TISSUE
  conforms_to: "osteoporosis_bone_resorption#Increased Osteoclastic Bone Resorption"
  description: >-
    The defining skeletal lesion. From the second decade, focal osteolytic
    lesions arise mainly in the limb bones, the tibia above all, and advance
    along the shaft. Progressive osteoclastic resorption is accompanied by
    medullary expansion and cortical thinning, so the bone widens as it
    weakens; the sequence ends in pain, severe deformity and pathological
    fracture. Unlike Paget disease, the lesion does not pass into a sclerotic
    phase: osteolysis progresses to fat-filled bone. Extensive peripheral and
    even skull involvement has been described in childhood-onset disease.
    Conforms to the module's central resorption effector with the caveat
    that here the resorption is focal and expansile rather than the diffuse
    trabecular loss of osteoporosis.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  locations:
  - preferred_term: long bones of the limbs
    term:
      id: UBERON:0002495
      label: long bone
  - preferred_term: tibia
    term:
      id: UBERON:0000979
      label: tibia
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive osteoclastic resorption is accompanied by medullary expansion which leads to pain, severe deformity and a tendency to pathological fracture."
    explanation: >-
      The original statement of the lesion's structure and its consequences,
      naming osteoclastic resorption, medullary expansion, pain, deformity and
      fracture in one sentence.
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity."
    explanation: >-
      Localises the lesions to the long bones and dates their onset.
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial expansile osteolysis (FEO) is a rare autosomal dominant disorder characterized by striking focal expansile osteolytic bone lesions and generalized osteopenia, often accompanied by characteristic early hearing loss and dental disease."
    explanation: >-
      Names the focal expansile osteolytic lesion as the characteristic
      feature against the generalised osteopenic background.
  - reference: PMID:16831914
    reference_title: "Paget's disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In FEO, osteolysis progresses to fat-filled bone rather than to osteosclerosis."
    explanation: >-
      The end state that distinguishes the FEO lesion from a Paget lesion.
      Evidence source is OTHER because this is a review.
  - reference: PMID:16470392
    reference_title: "Familial expansile osteolysis--not exclusively an adult disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her radiographic bone involvement was unusually extensive, involving most of the peripheral skeleton and the skull."
    explanation: >-
      The extreme of the distribution: a childhood-onset case with lesions
      through most of the peripheral skeleton and the skull.
  downstream:
  - target: Focal expansile osteolytic lesions of the long bones
    causal_link_type: DIRECT
    description: >-
      The radiographic phenotype of this node.
  - target: Bone pain
    causal_link_type: DIRECT
    description: >-
      Pain localised to active lesions.
  - target: Pathologic fracture
    causal_link_type: DIRECT
    description: >-
      Cortical thinning and expansion leave the bone unable to carry load.
  - target: Long bone deformity and bowing
    causal_link_type: DIRECT
    description: >-
      Expanded, thinned bone deforms under load.
- name: Middle-Ear Ossicular Resorption
  biological_scale: TISSUE
  description: >-
    The auditory ossicles are resorbed. Hereditary incus necrosis was the
    first ossicular lesion described in the Northern Irish family; a later
    family showed total absence of the middle-ear ossicles on temporal-bone
    CT and at exploratory surgery, with the hearing loss dating from
    childhood. Because the ossicles are among the smallest bones in the body,
    the same osteoclast overactivity that takes decades to hollow a tibia can
    remove them in the first years of life, which is why deafness is usually
    the first sign of the disease. The loss is conductive; a mixed component
    develops in some patients. Ossicular reconstruction has been reported not
    to improve thresholds.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  locations:
  - preferred_term: auditory ossicles
    term:
      id: UBERON:0001686
      label: auditory ossicle bone
  - preferred_term: middle ear
    term:
      id: UBERON:0001756
      label: middle ear
  evidence:
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The total absence of middle-ear ossicles can probably be regarded as a new symptom in some patients with familial expansile osteolysis."
    explanation: >-
      The extreme of the ossicular lesion: complete absence of the ossicles
      in three members of one family.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hearing loss was revealed in the medical histories since childhood."
    explanation: >-
      Dates the ossicular lesion to childhood.
  - reference: PMID:2530018
    reference_title: "Familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected members of the family have an associated early-onset deafness and loss of dentition as a result of unique middle ear and dental abnormalities."
    explanation: >-
      Attributes the early deafness to a middle-ear abnormality in the
      original kindred.
  downstream:
  - target: Early-onset conductive and mixed hearing loss
    causal_link_type: DIRECT
    description: >-
      Loss of the ossicular chain breaks sound conduction to the cochlea.
  - target: Absent or resorbed middle-ear ossicles
    causal_link_type: DIRECT
    description: >-
      The imaging and surgical finding of this node.
- name: External Root Resorption of Permanent Teeth
  biological_scale: TISSUE
  description: >-
    Cervical and apical external resorption of the roots of the permanent
    teeth, with premature deposition of irregular secondary dentine that
    narrows the pulp and of cellular cementum that narrows the periodontal
    ligament. Root resorption is an early manifestation, present in 16 of 20
    family members with skeletal disease in the Northern Irish study, and may
    precede bone involvement; the deciduous teeth are largely spared. The
    teeth loosen, fracture and are lost in adolescence. It is the dental
    expression of the same resorptive overactivity, and in a child it can be
    the presenting finding.
  biological_processes:
  - preferred_term: bone resorption (root and periodontal resorption)
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  locations:
  - preferred_term: roots of the permanent teeth
    term:
      id: UBERON:0001091
      label: calcareous tooth
  evidence:
  - reference: PMID:2216357
    reference_title: "Dental abnormalities associated with familial expansile osteolysis: a clinical and radiographic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-seven family members, aged 3 to 60 years, were examined clinically and radiographically, and it was found that cervical and/or apical root resorption is an early manifestation of the dysplasia."
    explanation: >-
      The clinical and radiographic dental study of the original kindred,
      establishing root resorption as an early manifestation.
  - reference: PMID:2216357
    reference_title: "Dental abnormalities associated with familial expansile osteolysis: a clinical and radiographic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 20 family members with skeletal manifestations of familial expansile osteolysis, 16 showed root resorption."
    explanation: >-
      The count behind the frequency of root resorption in affected members.
  - reference: PMID:2341974
    reference_title: "Dental histology in familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The predominant dental features are resorption of the cervical and apical regions of the roots, premature depositions both of irregular secondary dentin, which causes narrowing of the pulp cavities, and of cellular cementum, which causes patchy narrowing of the periodontal ligament."
    explanation: >-
      The histopathology of the dental lesion, showing that the tooth is
      remodelled as well as resorbed.
  downstream:
  - target: External root resorption of permanent teeth
    causal_link_type: DIRECT
    description: >-
      The dental phenotype of this node.
  - target: Premature loss of permanent teeth
    causal_link_type: DIRECT
    description: >-
      Resorbed roots loosen and the teeth are lost.
phenotypes:
- name: Focal expansile osteolytic lesions of the long bones
  category: Skeletal
  description: >-
    Progressive lytic lesions of the limb bones, most often the tibia, that
    begin from the second decade and advance along the shaft with medullary
    expansion and cortical thinning. They are the radiographic signature of
    the disease and, with the deafness and tooth loss, the basis of
    diagnosis. Expression is variable: some carriers have few or no
    lesions, while childhood-onset disease can involve most of the
    peripheral skeleton and the skull.
  phenotype_term:
    preferred_term: Focal expansile osteolysis of the appendicular skeleton
    term:
      id: HP:0002797
      label: Osteolysis
    onset:
      onset_category: JUVENILE
      notes: >-
        Focal skeletal lesions have their onset from the second decade in the
        original kindred; childhood onset is documented.
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease shows both general and focal skeletal changes, the latter being mainly in the limbs with an onset from the second decade."
    explanation: >-
      Places the focal lesions in the limbs and dates their onset to the
      second decade.
  - reference: PMID:17447113
    reference_title: "Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of FEO include early-onset hearing loss, tooth destruction, and progressive lytic expansion within limb bones causing pain, fracture, and deformity."
    explanation: >-
      Names progressive lytic expansion within the limb bones as a cardinal
      clinical feature.
  - reference: PMID:16470392
    reference_title: "Familial expansile osteolysis--not exclusively an adult disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case documents that familial expansile osteolysis is not only a disease of adults but does occur in childhood."
    explanation: >-
      Extends the onset range into childhood.
- name: Bone pain
  category: Skeletal
  description: >-
    Pain localised to active osteolytic lesions, often the presenting
    skeletal symptom; in the original kindred it accompanied the medullary
    expansion of the lesions.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive osteoclastic resorption is accompanied by medullary expansion which leads to pain, severe deformity and a tendency to pathological fracture."
    explanation: >-
      Names pain as a consequence of the expanding lesion.
  - reference: PMID:41264685
    reference_title: "A Novel Approach to the Treatment of Familial Expansile Osteolysis: A Rare Genetic Bone Pathology: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial expansile osteolysis (FEO) is a rare inherited autosomal dominant condition causing the development of painful lytic bone lesions."
    explanation: >-
      A recent case report characterises the lesions as painful.
- name: Pathologic fracture
  category: Skeletal
  description: >-
    Fracture through an expanded, cortically thinned lesion under ordinary
    load. Fractures generally unite, but recurrent fracture and deformity in
    advanced lesions have led to disability and, historically, amputation.
  phenotype_term:
    preferred_term: Pathologic fracture
    term:
      id: HP:0002756
      label: Pathologic fracture
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive osteoclastic resorption is accompanied by medullary expansion which leads to pain, severe deformity and a tendency to pathological fracture."
    explanation: >-
      Names the tendency to pathological fracture as a consequence of the
      lesion.
  - reference: PMID:2530018
    reference_title: "Familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive osteoclastic resorption accompanied by medullary expansion leads to severe and painful disabling deformities with a tendency to pathologic fracture."
    explanation: >-
      The 1989 kindred description restates fracture as part of the natural
      history.
- name: Long bone deformity and bowing
  category: Skeletal
  description: >-
    Severe, disabling deformity of the affected long bones as the expanded,
    thin-walled shaft bends under load. Bound to the general long-bone
    morphology term because the sources describe deformity of the limb bones
    without consistently specifying bowing.
  phenotype_term:
    preferred_term: Progressive deformity of the affected long bones
    term:
      id: HP:0011314
      label: Abnormal long bone morphology
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:2530018
    reference_title: "Familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive osteoclastic resorption accompanied by medullary expansion leads to severe and painful disabling deformities with a tendency to pathologic fracture."
    explanation: >-
      Describes the deformities as severe and disabling.
  - reference: PMID:17447113
    reference_title: "Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of FEO include early-onset hearing loss, tooth destruction, and progressive lytic expansion within limb bones causing pain, fracture, and deformity."
    explanation: >-
      Names deformity among the consequences of lytic expansion in the limb
      bones.
- name: Generalized osteopenia
  category: Skeletal
  description: >-
    Low bone mass across the skeleton, distinct from the focal lesions and
    reflecting the generalised acceleration of remodelling. Coarse,
    fish-net trabeculation has been described in the American kindred.
  phenotype_term:
    preferred_term: Generalized osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial expansile osteolysis (FEO) is a rare autosomal dominant disorder characterized by striking focal expansile osteolytic bone lesions and generalized osteopenia, often accompanied by characteristic early hearing loss and dental disease."
    explanation: >-
      Names generalised osteopenia as a characteristic feature alongside the
      focal lesions.
- name: Early-onset conductive and mixed hearing loss
  category: Auditory
  description: >-
    Hearing loss beginning in early childhood, usually the first sign of the
    disease and present in most affected members of the original kindred.
    It is conductive at first, from resorption of the ossicular chain, and a
    mixed conductive-sensorineural pattern develops in some patients.
    Ossicular reconstruction has not restored thresholds where the ossicles
    are absent.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Early-onset conductive, later mixed, hearing loss
    term:
      id: HP:0000405
      label: Conductive hearing impairment
    onset:
      onset_category: CHILDHOOD
      notes: >-
        Hearing loss is present from childhood; the deep-research report
        gives onset as early as age 4 in the classic kindred.
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients had an associated deafness of early onset and loss of dentition."
    explanation: >-
      Establishes both the early-onset deafness and its frequency: most
      patients in the 40-case kindred, which supports VERY_FREQUENT.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiometry indicated mild to moderate conductive and mixed hearing loss and also an AD-type tympanogram pattern along with an absence of acoustic reflexes in both ears of the cases."
    explanation: >-
      Audiometric characterisation as conductive and mixed loss.
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One had no family history of FEO, but presented with bilateral hearing loss at an early age, deterioration of teeth, and severe pain and swelling in the distal tibia before the age of 20."
    explanation: >-
      A sporadic case presenting with early bilateral hearing loss, showing
      the feature is not confined to the Northern Irish kindred.
- name: Absent or resorbed middle-ear ossicles
  category: Auditory
  description: >-
    Resorption of the ossicular chain. Hereditary incus necrosis was the
    first ossicular lesion described; in a later family the ossicles were
    entirely absent bilaterally on temporal-bone CT and at exploratory
    middle-ear surgery.
  phenotype_term:
    preferred_term: Absent or resorbed middle-ear ossicles
    term:
      id: HP:0004452
      label: Abnormality of the middle ear ossicles
  evidence:
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The temporal-bone computed-tomography scan in the coronal view of all three patients and also exploratory middle-ear surgery, which was done on two of the patients, showed no ossicles in the middle ear of either ear in all three cases."
    explanation: >-
      The imaging and surgical demonstration of complete ossicular absence.
  - reference: PMID:2530018
    reference_title: "Familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most affected members of the family have an associated early-onset deafness and loss of dentition as a result of unique middle ear and dental abnormalities."
    explanation: >-
      Attributes the deafness of the original kindred to a middle-ear
      abnormality.
- name: External root resorption of permanent teeth
  category: Dental
  description: >-
    Cervical and apical external resorption of the roots of the permanent
    teeth, an early manifestation that may precede skeletal disease and is a
    prognosticator for later bone involvement. Present in 16 of 20 members of
    the original kindred who had skeletal manifestations. Deciduous teeth are
    largely spared. In a child it may be the finding that leads to diagnosis.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: External cervical and apical root resorption of permanent teeth
    term:
      id: HP:0006486
      label: Abnormal dental root morphology
  evidence:
  - reference: PMID:2216357
    reference_title: "Dental abnormalities associated with familial expansile osteolysis: a clinical and radiographic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 20 family members with skeletal manifestations of familial expansile osteolysis, 16 showed root resorption."
    explanation: >-
      Sixteen of twenty affected members, 80 per cent, which supports the
      VERY_FREQUENT band.
  - reference: PMID:2216357
    reference_title: "Dental abnormalities associated with familial expansile osteolysis: a clinical and radiographic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Root resorption may therefore be a good prognosticator for later bone involvement."
    explanation: >-
      Root resorption precedes and predicts skeletal disease.
  - reference: PMID:32075714
    reference_title: "Multiple External Root Resorption in a Pediatric Patient with Familial Expansile Osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was not diagnosed with FEO until the age of 10 years, when she presented to the dental clinic with advanced ERR in several permanent teeth."
    explanation: >-
      A child in whom advanced external root resorption was the presenting
      finding.
- name: Premature loss of permanent teeth
  category: Dental
  description: >-
    Loss of the permanent dentition in adolescence and early adulthood as
    resorbed roots loosen and teeth fracture. Present in most affected
    members of the original kindred.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Premature loss of permanent teeth
    term:
      id: HP:0006480
      label: Premature loss of teeth
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients had an associated deafness of early onset and loss of dentition."
    explanation: >-
      Loss of dentition in most patients of the 40-case kindred, supporting
      the VERY_FREQUENT band.
  - reference: PMID:17447113
    reference_title: "Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features of FEO include early-onset hearing loss, tooth destruction, and progressive lytic expansion within limb bones causing pain, fracture, and deformity."
    explanation: >-
      Tooth destruction as a cardinal clinical feature.
- name: Elevated serum alkaline phosphatase
  category: Laboratory
  description: >-
    Serum alkaline phosphatase is variably elevated, reflecting the
    osteoblastic arm of accelerated remodelling. It tracks disease activity
    and antiresorptive response, but is not uniformly high: a child with an
    allelic 12-bp duplication had values in the upper normal range.
  phenotype_term:
    preferred_term: Elevated serum alkaline phosphatase
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."
    explanation: >-
      The original biochemical description: variably elevated alkaline
      phosphatase with other indices normal.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both serum alkaline phosphatase and hydroxyproline levels were elevated."
    explanation: >-
      Elevated alkaline phosphatase in a second, unrelated family.
- name: Hydroxyprolinuria
  category: Laboratory
  description: >-
    Urinary hydroxyproline, the classic collagen-breakdown marker of bone
    resorption, is variably raised. Newer resorption markers such as urinary
    N-telopeptide are raised in the allelic disorders and are the modern
    equivalent.
  phenotype_term:
    preferred_term: Elevated urinary hydroxyproline
    term:
      id: HP:0003080
      label: Hydroxyprolinuria
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."
    explanation: >-
      Names urinary hydroxyproline as variably elevated.
  - reference: PMID:2530018
    reference_title: "Familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The serum alkaline phosphatase and urinary hydroxyproline are elevated to a variable degree, whereas other biochemical indices are normal."
    explanation: >-
      The 1989 description restates the elevated urinary hydroxyproline.
- name: Osteosarcoma
  category: Neoplastic
  description: >-
    Osteogenic sarcoma has been reported in a 17-year-old from an affected
    family, with a chondroblastic tumour of the iliac bone, and the deep
    research report notes a further familial report; the authors speculate
    that the high turnover facilitates sarcoma, as in Paget disease. The
    absolute risk is unknown and the association rests on isolated cases, so
    no frequency is assigned.
  phenotype_term:
    preferred_term: Osteosarcoma
    term:
      id: HP:0002669
      label: Osteosarcoma
  evidence:
  - reference: PMID:20168251
    reference_title: "Osteogenic sarcoma in a child with familial expansile osteolysis syndrome: an accidental association?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present the first reported case of a child with familial expansile osteolysis syndrome (FEO) who developed osteogenic sarcoma (OS) of the iliac bone."
    explanation: >-
      The first reported case; the title's question mark and the single case
      are why this phenotype carries no frequency.
  - reference: PMID:20168251
    reference_title: "Osteogenic sarcoma in a child with familial expansile osteolysis syndrome: an accidental association?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also think that increased bone turnover, characteristic of a condition such as FEO, may facilitate de novo development of OS."
    explanation: >-
      The authors' mechanistic speculation, recorded as speculation.
histopathology:
- name: Osteoclast-rich resorption with increased osteoclast number and multinuclearity
  description: >-
    Affected bone shows an increase in osteoclast number, in the number of
    nuclei per osteoclast and in osteoclast activity, with coupled osteoblast
    activity, the histological picture of a high-turnover osteoclast-driven
    lesion. This is the tissue basis of the pathophysiology node
    "Constitutive Osteoclast Formation, Survival and Activation". The bound
    NCIT term covers the increase in osteoclast number; the multinuclearity
    and activity components are carried by the preferred term and the quoted
    evidence.
  finding_term:
    preferred_term: increased osteoclast number and multinuclearity
    term:
      id: NCIT:C147498
      label: Increased Osteoclasts
  evidence:
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity."
    explanation: >-
      The histological observation in patients' lesions of increased
      osteoclast and osteoblast activity.
  - reference: PMID:21472776
    reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Affected areas show an increase in osteoclast number, multinuclearity, and activity, which leads to the notion that these diseases are driven by osteoclast overactivity, as is classic late-onset Paget disease of bone."
    explanation: >-
      The count, multinuclearity and activity components of the finding.
      The sentence is the introduction's summary of the published human
      histology of the RANK signal-peptide disorders rather than a result of
      the paper's own in vitro experiments, so the evidence it describes is
      human clinical and the quote role records that this paper is not its
      source.
  notes: >-
    The primary histological descriptions of the Northern Irish kindred are
    not cached with an abstract that states the microscopic findings, so the
    finer features reported in the literature (woven trabeculae, vascular
    fibrous marrow, and the absence of the mosaic lamellar pattern of Paget
    disease) are not curated here; only what the cached sources state is
    recorded.
- name: Fibrous and then fatty replacement of the medulla at the end stage of a lesion
  description: >-
    The advancing lytic lesion destroys the medullary bone, which is replaced
    first by fibrous tissue and finally by fat, so that the burnt-out lesion is
    a thin-walled, fat-filled shell rather than the sclerotic bone of a late
    Paget lesion. The same fibrous replacement is seen in the middle ear,
    where the incus is replaced by fibrous tissue. Left unbound because no
    NCIT morphologic-finding term covers the fibrous-to-fatty sequence of
    medullary replacement: NCIT:C36212 (Bone Marrow Fibrosis) is in the
    histopathology branch but names only the fibrous stage, and binding it
    would misdescribe the fat-filled end state that defines the finding. The
    two sources quoted are a radiographic series and a review, and the
    finding is recorded here because it is the tissue end state the
    radiographs and the reviews describe.
  evidence:
  - reference: PMID:2353208
    reference_title: "The radiographic features of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal features comprise lytic areas which progressively enlarge, producing expansion of the bone and eventual disintegration due to fibrous and finally fatty replacement of the normal medulla."
    explanation: >-
      The radiographic series of the original kindred describes the sequence
      of fibrous and then fatty replacement of the medulla.
  - reference: PMID:16831914
    reference_title: "Paget's disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In FEO, osteolysis progresses to fat-filled bone rather than to osteosclerosis."
    explanation: >-
      Review statement of the fat-filled end state and its contrast with
      Paget sclerosis. Evidence source is OTHER because this is a review.
  - reference: PMID:30756140
    reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A characteristic feature on otological examination was replacement of the incus by fibrous tissue."
    explanation: >-
      The fibrous replacement of resorbed bone seen at the incus. Evidence
      source is OTHER because this is a review.
genetic:
- name: TNFRSF11A
  gene_term:
    preferred_term: TNFRSF11A
    term:
      id: hgnc:11908
      label: TNFRSF11A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Encodes RANK (receptor activator of NF-kappaB), the TNF receptor
    superfamily member on osteoclast precursors that binds RANKL (TNFSF11,
    hgnc:11926) and is essential for osteoclast formation. Mutation spectrum
    in FEO: a heterozygous in-frame 18-bp tandem duplication in exon 1,
    84dup18, in every FEO kindred reported, plus a second 18-bp duplication
    one base proximal in two unrelated patients; both add the same six
    residues to the signal peptide. Intragenic haplotypes show at least three
    independent origins for the recurrent duplication. The allelic
    signal-peptide duplications, 27-bp (PDB2), 15-bp (ESH, and JPD2 at
    87dup15) and 12-bp (PEBD), cause the related disorders described in the
    entry notes; a 2023 report of the 12-bp duplication arising de novo shows
    that these duplications can occur without family history. The
    duplications are activating in the sense of producing a heterozygous
    high-turnover phenotype and increased NF-kappaB signalling on
    overexpression; biallelic loss of function of the same gene causes
    osteoclast-poor osteopetrosis, so the disease is not a dosage effect of
    the receptor but a consequence of the misprocessed protein. No ClinGen
    gene-disease validity assertion for TNFRSF11A and FEO was found in the
    cached ClinGen records.
  evidence:
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB)."
    explanation: >-
      The gene discovery in affected members of four families.
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RANK is essential in osteoclast formation."
    explanation: >-
      The function of the gene product that makes the lesion an osteoclast
      disease.
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identical insertional mutations in the first exon of RANK have been identified in all published FEO kindreds."
    explanation: >-
      The recurrence of the same mutation across all kindreds published to
      2003.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 18-bp duplication in TNFRSF11A has been reported in all kindreds with FEO, whereas a 12-bp duplication was found in the young man with PEBD complicated by a massive jaw tumor."
    explanation: >-
      A 2023 restatement that the 18-bp duplication defines FEO, contrasted
      with the 12-bp allele of the panostotic disorder.
  - reference: PMID:25063546
    reference_title: "Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients with autosomal dominant accelerated bone remodeling have familial expansile osteolysis, early-onset Paget's disease of bone, expansile skeletal hyperphosphatasia, or panostotic expansile bone disease due to heterozygous 18-, 27-, 15-, and 12-bp insertional duplications, respectively, within exon 1 of TNFRSF11A that encodes the signal peptide of RANK."
    explanation: >-
      The allelic series in one sentence, mapping duplication length to
      disorder.
  - reference: PMID:11771666
    reference_title: "Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hence, ESH and FEO are allelic diseases and ESH, like FEO, probably reflects increased activity in the skeleton of the RANK target, nuclear factor-kappaB (NF-kappaB)."
    explanation: >-
      Establishes ESH as allelic to FEO and records the shared inference of
      increased NF-kappaB activity.
  - reference: PMID:17447113
    reference_title: "Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 18-bp duplication in the first exon of the TNFRSF11A gene encoding RANK has been previously identified in four FEO pedigrees."
    explanation: >-
      Counts the pedigrees carrying the 18-bp duplication before the Iranian
      family was added.
biochemical:
- name: Elevated serum alkaline phosphatase
  presence: Variably elevated
  context: >-
    Total or bone-specific alkaline phosphatase is the routine marker of the
    generalised high turnover and of response to antiresorptive treatment.
    It is variably raised and can be in the upper normal range in mild or
    early disease, so a normal value does not exclude the diagnosis.
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."
    explanation: >-
      The original biochemical profile.
  - reference: PMID:16831914
    reference_title: "Paget's disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Biochemical markers indicate rapid skeletal remodeling."
    explanation: >-
      Review statement that the markers read out rapid remodelling.
      Evidence source is OTHER because this is a review.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Biochemical studies indicated increased bone turnover with elevated urinary N-telopeptide levels and serum alkaline phosphatase in the upper normal range."
    explanation: >-
      Shows that alkaline phosphatase can sit in the upper normal range
      while resorption markers are raised. Indirect because the patient
      carried the allelic 12-bp duplication rather than the FEO allele.
- name: Elevated urinary bone resorption markers
  presence: Variably elevated
  context: >-
    Urinary hydroxyproline in the original descriptions; urinary
    N-telopeptide and other collagen crosslink markers in later reports of
    the allelic disorders. These are the markers used to titrate
    antiresorptive therapy.
  evidence:
  - reference: PMID:2530018
    reference_title: "Familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The serum alkaline phosphatase and urinary hydroxyproline are elevated to a variable degree, whereas other biochemical indices are normal."
    explanation: >-
      The resorption marker in the original kindred.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Biochemical studies indicated increased bone turnover with elevated urinary N-telopeptide levels and serum alkaline phosphatase in the upper normal range."
    explanation: >-
      Urinary N-telopeptide as the modern resorption marker; indirect
      because the case carries the allelic 12-bp duplication.
- name: Normal serum calcium and phosphate
  presence: Normal in untreated FEO
  context: >-
    Calcium, phosphate and the other routine indices are normal in FEO, which
    is one of the features that separates it from the allelic expansile
    skeletal hyperphosphatasia, where episodic hypercalcaemia occurs, and from
    immobilisation hypercalcaemia in the juvenile Paget phenotype. After
    potent antiresorptive treatment, prolonged hypocalcaemia is the hazard.
  evidence:
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The serum alkaline phosphatase and urinary hydroxyproline are variably elevated, while other biochemical indices are normal."
    explanation: >-
      The other biochemical indices, including calcium, are normal.
  - reference: PMID:11771666
    reference_title: "Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Absence of large osteolytic lesions with cortical thinning in major long bones, together with bouts of hypercalcemia, indicated that ESH is not a variant of familial expansile osteolysis (FEO)."
    explanation: >-
      The contrast that defines the boundary: hypercalcaemia belongs to ESH,
      and its absence in FEO was one of the two features used to separate the
      disorders.
diagnosis:
- name: Clinical Recognition of the Deafness, Root Resorption and High-Turnover Osteolysis Triad
  diagnosis_term:
    preferred_term: Clinical Evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  description: >-
    The diagnosis is suspected from the stereotyped sequence: conductive
    hearing loss from early childhood, external root resorption and premature
    loss of the permanent teeth in adolescence, and from the second decade
    painful expansile osteolytic lesions of the limb bones on a background of
    raised bone-turnover markers with normal calcium and phosphate. A family
    history compatible with autosomal dominant transmission strengthens the
    suspicion but sporadic cases occur, and in a child the presenting finding
    is usually the deafness or unexplained multiple root resorption at the
    dental clinic. No consensus diagnostic criteria exist; recognition of the
    pattern is what prompts the imaging and molecular workup below.
  results: >-
    A compatible clinical pattern that triggers biochemical, imaging and
    TNFRSF11A testing; not by itself diagnostic.
  evidence:
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Constitutive activation of RANK signaling should be considered a possible cause in any young person with rapid bone turnover, particularly in the context of early-onset deafness and/or root resorption of permanent teeth."
    explanation: >-
      The authors' diagnostic rule for the whole RANK signal-peptide series,
      naming the triad of rapid turnover, early deafness and root resorption
      as the trigger for suspecting the disorder.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FEO typically presents with childhood-onset deafness followed by resorption of permanent dentition, and then appendicular bone pain, fractures, and deformities from progressive focal expansile osteolytic lesions emerging from a background of generalized high bone turnover."
    explanation: >-
      The clinical sequence on which recognition rests.
  - reference: PMID:32075714
    reference_title: "Multiple External Root Resorption in a Pediatric Patient with Familial Expansile Osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was not diagnosed with FEO until the age of 10 years, when she presented to the dental clinic with advanced ERR in several permanent teeth."
    explanation: >-
      A child born with missing ossicles whose diagnosis was only made when
      root resorption brought her to the dental clinic, which is why dental
      presentation is named as a route to recognition.
- name: Skeletal Radiography
  diagnosis_term:
    preferred_term: plain radiography of the limb bones
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  description: >-
    Plain radiographs of symptomatic sites, or a skeletal survey, show the two
    classes of change described in the original kindred: generalised
    alteration of the trabecular pattern and modelling of the long bones,
    which can be seen before any focal lesion, and focal lytic areas that
    enlarge along the shaft, expand the bone and thin the cortex until the
    medulla is replaced by fibrous and then fatty tissue. The distribution is
    the discriminating feature: almost all lesions are appendicular, and the
    pelvis, spine and skull that classic Paget disease favours are spared.
    Radiographs are also how lesion advance, fracture and response to
    treatment are followed.
  results: >-
    Appendicular expansile lytic lesions with medullary expansion and cortical
    thinning, with or without generalised trabecular coarsening; the axial
    skeleton is spared. The radiological differential is Paget disease,
    polyostotic fibrous dysplasia and osteofibrous dysplasia.
  evidence:
  - reference: PMID:2353208
    reference_title: "The radiographic features of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalised features are either altered trabecular pattern or modelling abnormalities."
    explanation: >-
      The generalised radiographic changes of the original kindred.
  - reference: PMID:2353208
    reference_title: "The radiographic features of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal features comprise lytic areas which progressively enlarge, producing expansion of the bone and eventual disintegration due to fibrous and finally fatty replacement of the normal medulla."
    explanation: >-
      The focal radiographic lesion and its evolution.
  - reference: PMID:2353208
    reference_title: "The radiographic features of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiologically, the differential diagnosis refers to Paget's disease, polyostotic fibrous dysplasia, and osteofibrous dysplasia."
    explanation: >-
      The radiological differential named by the radiographic series.
  - reference: PMID:30756140
    reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Osterberg commented that abnormalities in the trabecular pattern of bone on x-rays could be identified affecting the humerus, radius, ulna and tibia, before osteolytic lesions develop."
    explanation: >-
      Trabecular change on radiographs precedes the focal lesions, so
      radiography can show disease before a lytic lesion exists. Evidence
      source is OTHER because this is a review.
  - reference: PMID:30756140
    reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In contrast to classical PDB, the pelvis, spine and skull were unaffected."
    explanation: >-
      The axial sparing that separates FEO from Paget disease on a skeletal
      survey. Evidence source is OTHER because this is a review.
  - reference: PMID:41264685
    reference_title: "A Novel Approach to the Treatment of Familial Expansile Osteolysis: A Rare Genetic Bone Pathology: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient's progress was monitored with radiographs, magnetic resonance imaging, bone turnover markers, pain, and functional scores."
    explanation: >-
      Radiographs and MRI as the monitoring tools in the recent treatment
      report.
- name: Technetium-99m Bone Scintigraphy
  diagnosis_term:
    preferred_term: whole-body technetium-99m bone scintigraphy
    term:
      id: NCIT:C17646
      label: Bone Scan
  description: >-
    Whole-body radionuclide bone scan maps the extent of disease: tracer
    uptake is increased at focal osteolytic lesions and, in the original
    kindred, in the tibiae of patients who had no focal lesion, reflecting
    the generalised high turnover. It is the imaging test that shows the
    multifocal, polyostotic nature of the disease in one study and identifies
    lesions before they are symptomatic. A normal scan does not exclude a
    signal-peptide duplication: a child with the allelic 12-bp duplication
    and mild disease had a normal scan despite raised resorption markers.
  results: >-
    Increased tracer uptake at multiple appendicular foci, sometimes with
    diffusely increased uptake in the tibiae without a focal lesion; may be
    normal in early or mild disease.
  evidence:
  - reference: PMID:30756140
    reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Radionuclide bone scans show increased tracer uptake at the site of focal osteolytic lesions."
    explanation: >-
      The scintigraphic finding at focal lesions. Evidence source is OTHER
      because this is a review.
  - reference: PMID:30756140
    reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In addition, tracer uptake was reported to be increased in the tibiae of patients without focal bone lesions in keeping a generalized elevation in bone turnover."
    explanation: >-
      Increased uptake without a focal lesion, which is the scintigraphic
      readout of the generalised remodelling. Evidence source is OTHER
      because this is a review.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was an increase in uptake and activity at multiple foci of the whole skeleton."
    explanation: >-
      Whole-body Tc-99m MDP scans in three affected family members showing
      multifocal increased uptake.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each patient underwent computerized tomography of the temporal bone in the coronal view, audiometric and tympanometric evaluations, biochemical investigation, whole body isotope scans by Tc-99 mMDP and X-ray."
    explanation: >-
      The workup actually performed in a reported family: temporal-bone CT,
      audiometry, biochemistry, whole-body isotope scan and radiography.
  - reference: PMID:36740137
    reference_title: "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."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Low lumbar spine bone mineral density (BMD) was revealed by dual-energy X-ray absorptiometry, but whole-body Technetium-99 m bone scintigraphy was normal."
    explanation: >-
      Recorded as REFUTE of scintigraphy as a sensitive test for early
      disease: a child with raised turnover markers and low bone density had
      a normal scan. Indirect because she carried the allelic 12-bp
      duplication rather than the FEO allele.
- name: Panoramic Dental Radiography and Cone-Beam CT for Root Resorption
  diagnosis_term:
    preferred_term: panoramic dental radiography and cone-beam CT
    term:
      id: NCIT:C150663
      label: Orthopantomogram
  description: >-
    Clinical and radiographic dental examination detects cervical and apical
    external root resorption of the permanent teeth, which is an early
    manifestation, precedes skeletal disease in many patients and predicts
    later bone involvement. A panoramic radiograph is the screening view;
    cone-beam CT resolves the extent of resorption of individual roots and is
    the modality on which progression has been followed. Multiple external
    root resorption with no local cause in a child should prompt the systemic
    and genetic evaluation recorded below. Cone-beam CT is carried in the
    preferred term because the schema binds one procedure term per
    diagnostic item; NCIT:C71695 is its identifier.
  results: >-
    Cervical and/or apical external root resorption of several permanent
    teeth, with narrowed pulp chambers from irregular secondary dentine;
    deciduous teeth largely spared.
  evidence:
  - reference: PMID:2216357
    reference_title: "Dental abnormalities associated with familial expansile osteolysis: a clinical and radiographic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-seven family members, aged 3 to 60 years, were examined clinically and radiographically, and it was found that cervical and/or apical root resorption is an early manifestation of the dysplasia."
    explanation: >-
      The dental radiographic study of the original kindred, which
      established root resorption as an early, radiographically detectable
      manifestation.
  - reference: PMID:2216357
    reference_title: "Dental abnormalities associated with familial expansile osteolysis: a clinical and radiographic study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Root resorption may therefore be a good prognosticator for later bone involvement."
    explanation: >-
      Why a dental finding belongs in the diagnostic workup: it predicts the
      skeletal disease.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Panoramic dental radiographs had disclosed root resorption of the permanent maxillary and mandibular central incisors with ongoing concerns for early loss of her permanent teeth"
    explanation: >-
      The panoramic radiograph as the view that disclosed the resorption;
      indirect because the child carried the allelic 12-bp duplication.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "cone beam computed tomography (CBCT) scan images showed continued root resorption of the permanent maxillary and mandibular central incisors"
    explanation: >-
      Cone-beam CT as the modality on which progression of the resorption
      was followed; indirect for the same reason.
- name: Temporal-Bone CT and MRI with Audiometry
  diagnosis_term:
    preferred_term: high-resolution temporal-bone CT with MRI and audiometry
    term:
      id: NCIT:C17204
      label: Computed Tomography
  description: >-
    Audiometry and tympanometry characterise the hearing loss, which is
    conductive at first and later mixed, and coronal high-resolution CT of
    the temporal bones shows the state of the ossicular chain, from
    hypoplastic and dysmorphic ossicles to their complete absence. MRI adds
    the inner ear and soft tissue. The imaging matters for management as well
    as diagnosis: where the ossicles are absent, ossicular reconstruction has
    not improved thresholds, so the finding steers rehabilitation toward
    amplification or implantation rather than ossiculoplasty.
  results: >-
    Conductive or mixed hearing loss with a type AD tympanogram and absent
    acoustic reflexes; hypoplastic, dysmorphic or absent middle-ear ossicles
    on temporal-bone CT.
  evidence:
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The temporal-bone computed-tomography scan in the coronal view of all three patients and also exploratory middle-ear surgery, which was done on two of the patients, showed no ossicles in the middle ear of either ear in all three cases."
    explanation: >-
      Coronal temporal-bone CT demonstrating the ossicular lesion, confirmed
      at surgery.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiometry indicated mild to moderate conductive and mixed hearing loss and also an AD-type tympanogram pattern along with an absence of acoustic reflexes in both ears of the cases."
    explanation: >-
      The audiometric and tympanometric profile.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "High resolution computed tomography (CT) and magnetic resonance imaging (MRI) of the temporal bones showed the handle of the malleus was present bilaterally"
    explanation: >-
      CT and MRI of the temporal bones used to define the ossicular
      abnormality; indirect because the child carried the allelic 12-bp
      duplication.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Bilaterally, the incus was very hypoplastic and dysmorphic, and the stapes was not well visualized."
    explanation: >-
      The imaging finding short of complete absence: hypoplastic, dysmorphic
      ossicles. Indirect for the same reason.
- name: TNFRSF11A Exon 1 Duplication Testing
  diagnosis_term:
    preferred_term: duplication-sensitive sequencing of TNFRSF11A exon 1
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Molecular confirmation is a heterozygous in-frame 18-bp tandem duplication
    in exon 1 of TNFRSF11A, found in every FEO kindred published. Because the
    lesion is a small tandem duplication in a GC-rich repeated sequence,
    the assay must be duplication-sensitive: Sanger sequencing of exon 1 in
    both directions, or a skeletal-dysplasia panel that provides
    deletion/duplication analysis alongside sequencing, detects it; a
    pipeline that does not resolve small tandem duplications can miss it. The
    length of the duplication identifies the allelic disorder (27 bp for
    early-onset familial Paget disease, 15 bp for expansile skeletal
    hyperphosphatasia, 12 bp for panostotic expansile bone disease), so the
    test also settles the differential among the RANK signal-peptide
    disorders. Parental testing distinguishes inherited from de novo
    duplications, and cascade testing identifies at-risk relatives before
    skeletal lesions form. Unexplained multiple external root resorption in a
    child is a recognised trigger for testing.
  results: >-
    Heterozygous 84dup18, or the one-base-shifted 18-bp duplication, in exon 1
    of TNFRSF11A.
  evidence:
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB)."
    explanation: >-
      The discovery study locating the diagnostic lesion in exon 1.
  - reference: PMID:12568416
    reference_title: "Identification of a novel tandem duplication in exon 1 of the TNFRSF11A gene in two unrelated patients with familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identical insertional mutations in the first exon of RANK have been identified in all published FEO kindreds."
    explanation: >-
      The recurrence of the same lesion across kindreds is what makes exon 1
      testing a confirmatory test rather than a research finding.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 18-bp duplication in TNFRSF11A has been reported in all kindreds with FEO, whereas a 12-bp duplication was found in the young man with PEBD complicated by a massive jaw tumor."
    explanation: >-
      Duplication length as the discriminator among the allelic disorders.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "which provides both sequencing and deletion/duplication analysis, revealed the same heterozygous 12-bp tandem duplication of TNFRSF11A"
    explanation: >-
      A clinical panel with duplication analysis detecting a signal-peptide
      duplication; indirect because the allele was the 12-bp one, but the
      assay requirement is the same for the 18-bp FEO allele.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Parental genetic testing at the same laboratory for the duplication was negative, indicating that her duplication occurred de novo."
    explanation: >-
      Parental testing to classify the duplication as inherited or de novo;
      indirect for the same reason.
  - reference: PMID:32075714
    reference_title: "Multiple External Root Resorption in a Pediatric Patient with Familial Expansile Osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is recommended that when ERR cannot be explained by local etiologic factors, systemic abnormalities and genetic testing should be considered."
    explanation: >-
      The dental recommendation that unexplained external root resorption
      should trigger systemic evaluation and genetic testing.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Nitrogen-containing bisphosphonates are the mainstay. Intravenous
    zoledronic acid or pamidronate, or oral alendronate, suppress the
    biochemical markers of turnover for prolonged periods and in the allelic
    disorders have mineralised early lesions and improved bone density;
    the first-generation agents etidronate and clodronate gave only transient
    responses, which is why aminobisphosphonates are preferred. Whether
    treatment changes the natural history of established lesions, deafness
    or tooth loss is uncertain: in early-onset Paget disease the biochemical
    response was not matched by clinical benefit for deformity, deafness or
    tooth loss, and the strongest argument for early treatment is a single
    child with a 12-bp duplication who developed no focal lesions on
    alendronate. In the 75dup27 mouse, zoledronic acid completely prevented
    lesion development. The specific hazard is prolonged hypocalcaemia after
    potent intravenous dosing in a high-turnover skeleton, so calcium and
    vitamin D are replete before treatment and calcium is monitored after
    it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
    therapeutic_agent:
    - preferred_term: zoledronic acid
      term:
        id: CHEBI:46557
        label: zoledronic acid
    - preferred_term: pamidronate
      term:
        id: CHEBI:7903
        label: pamidronate
    - preferred_term: alendronate
      term:
        id: CHEBI:2567
        label: alendronic acid
  target_mechanisms:
  - target: Constitutive Osteoclast Formation, Survival and Activation
    treatment_effect: INHIBITS
    description: >-
      Bisphosphonates act on the osteoclast directly, inducing its apoptosis
      and inhibiting resorption downstream of RANK, so they bypass the
      question of whether the receptor's signalling is ligand-dependent.
    evidence:
    - reference: PMID:33724536
      reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Treatment of these mice with zoledronic acid completely prevented the development of lesions."
      explanation: >-
        Prevention of focal lesions by an osteoclast-targeted drug in the
        knock-in mouse; indirect because the allele is the PDB2 duplication.
    - reference: PMID:30756140
      reference_title: "Rare Inherited forms of Paget's Disease and Related Syndromes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Bisphosphonates have been successfully used to gain control of elevated bone remodelling but as yet, no effective treatment exists for the treatment of the muscle and neurological manifestations of MSP syndromes."
      explanation: >-
        Review conclusion that bisphosphonates control the elevated
        remodelling in these disorders. Evidence source is OTHER because
        this is a review.
  evidence:
  - reference: PMID:16831914
    reference_title: "Paget's disease of bone and genetic disorders of RANKL/OPG/RANK/NF-kappaB signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Antiresorptive therapy with bisphosphonates can be effective for each disorder."
    explanation: >-
      Review statement covering FEO and its allelic disorders. Evidence
      source is OTHER because this is a review.
  - reference: PMID:18328984
    reference_title: "Juvenile Paget's disease, familial expansile osteolysis and other genetic osteolytic disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Anecdotal reports indicate that osteoclast inhibitors such as bisphosphonates are effective for suppressing bone turnover and improving symptoms in these disorders, although the long-term effects on clinical outcomes are unclear."
    explanation: >-
      Both the efficacy on turnover and the uncertainty about long-term
      clinical outcome, from a review. Evidence source is OTHER.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Bisphosphonate treatment, initiated with one dose of intravenous zoledronic acid that caused prolonged hypocalcemia, then comprised weekly oral alendronate that decreased bone turnover markers and normalized her BMD."
    explanation: >-
      The zoledronate hypocalcaemia hazard and the alendronate response in
      one sentence. Indirect because the child carried the allelic 12-bp
      duplication.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Early diagnosis and anti-resorptive treatment, given judiciously to avoid sudden and prolonged hypocalcemia, may prevent further skeletal disease."
    explanation: >-
      The authors' recommendation for early, cautious treatment; indirect
      for the same reason.
  - reference: PMID:18836673
    reference_title: "Clinical and biochemical response of TNFRSF11A-mediated early-onset familial Paget disease to bisphosphonate therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "In contrast, treatment with aminobisphosphonates resulted in greater suppression of biochemical markers of bone turnover with an extended duration of response."
    explanation: >-
      Aminobisphosphonates outperform etidronate on turnover markers in the
      allelic early-onset Paget disease; indirect because of the allele.
  - reference: PMID:18836673
    reference_title: "Clinical and biochemical response of TNFRSF11A-mediated early-onset familial Paget disease to bisphosphonate therapy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "From a clinical perspective, the results were less impressive and there was no clear benefit from antiresorptive treatment in terms of bone deformity, deafness, and tooth loss, although bone pain improved in one patient."
    explanation: >-
      Recorded as REFUTE of a clinical-benefit claim: in the allelic
      disorder the biochemical response did not translate into benefit for
      deformity, deafness or tooth loss.
  - reference: PMID:24014458
    reference_title: "Panostotic expansile bone disease with massive jaw tumor formation and a novel mutation in the signal peptide of RANK."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity."
    explanation: >-
      Biochemical response to alendronate and pamidronate in the 12-bp
      panostotic disorder; indirect because of the allele.
  - reference: PMID:2530018
    reference_title: "Familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The response of the disease to a therapeutic trial using parenteral dichloro-methylene-diphosphonate (dichloro-MDP) produced an initial rapid biochemical response, which was not sustained."
    explanation: >-
      The historical clodronate trial in the original kindred: a rapid but
      unsustained biochemical response, which is the reason first-generation
      agents were superseded.
- name: Denosumab
  description: >-
    The anti-RANKL monoclonal antibody, reported in a single adult with FEO in
    2025, in whom it improved the radiological appearance of affected bone
    and quality of life and permitted limb-salvage surgery in place of
    amputation. Its use is mechanistically interesting rather than
    established: if the mutant receptor signals independently of ligand,
    blocking the ligand should do little, so a response implies that
    osteoclast activity in FEO retains a RANKL-dependent component. The
    same hypocalcaemia caution as for bisphosphonates applies, and rebound
    turnover on withdrawal is a known property of the drug in other
    settings.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: denosumab
      term:
        id: NCIT:C61313
        label: Denosumab
  target_mechanisms:
  - target: Constitutive Osteoclast Formation, Survival and Activation
    treatment_effect: INHIBITS
    description: >-
      Neutralises RANKL, removing the ligand-dependent contribution to
      osteoclast formation and survival. The size of that contribution in
      FEO is the open question recorded in the discussions.
    evidence:
    - reference: PMID:41264685
      reference_title: "A Novel Approach to the Treatment of Familial Expansile Osteolysis: A Rare Genetic Bone Pathology: A Case Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The use of denosumab for FEO displays improvement in radiological appearances of the affected bone, increased quality of life and may prevent the development of further lesions."
      explanation: >-
        A radiological and clinical response in one patient, which is the
        whole of the evidence that ligand blockade acts on the lesion.
  evidence:
  - reference: PMID:41264685
    reference_title: "A Novel Approach to the Treatment of Familial Expansile Osteolysis: A Rare Genetic Bone Pathology: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present the case of a 54-year-old man with FEO who was treated with denosumab."
    explanation: >-
      The single published use of denosumab in FEO.
  - reference: PMID:41264685
    reference_title: "A Novel Approach to the Treatment of Familial Expansile Osteolysis: A Rare Genetic Bone Pathology: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a safe treatment modality for patients with FEO that allows for limb salvage surgery rather than amputation."
    explanation: >-
      The authors' conclusion on safety and on enabling limb salvage; a
      single-case conclusion, recorded as such.
- name: Orthopaedic Stabilisation and Limb Salvage Surgery
  description: >-
    Fracture fixation, stabilisation or correction of deformed expanded
    bones, and limb-salvage reconstruction for lesions that have destroyed
    the shaft. Historically, severe disease led to amputation; the 2025
    denosumab case reports that antiresorptive control made limb salvage
    possible instead. Surgery on active lesions has been observed to
    accelerate their extension, so operations are planned with turnover
    controlled where possible.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopaedic stabilisation and limb salvage surgery
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Pathologic fracture
    term:
      id: HP:0002756
      label: Pathologic fracture
  - preferred_term: Progressive deformity of the affected long bones
    term:
      id: HP:0011314
      label: Abnormal long bone morphology
  evidence:
  - reference: PMID:41264685
    reference_title: "A Novel Approach to the Treatment of Familial Expansile Osteolysis: A Rare Genetic Bone Pathology: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a safe treatment modality for patients with FEO that allows for limb salvage surgery rather than amputation."
    explanation: >-
      Places limb salvage surgery, and amputation as its historical
      alternative, in the management of advanced lesions.
- name: Hearing Rehabilitation with Cochlear Implantation
  description: >-
    Amplification and, for profound or mixed loss, cochlear implantation.
    Ossicular reconstruction is the intuitive operation for a conductive
    loss but has not improved thresholds where the ossicles are absent, and
    surgeons are warned of that. A child with an allelic 12-bp duplication
    was implanted at age 3 after conductive and sensorineural loss was found
    on evaluation for speech delay. The device is carried as a qualifier so
    that the cochlear implant remains queryable while the bound term stays a
    clinical action.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: cochlear device implantation and auditory rehabilitation
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  target_phenotypes:
  - preferred_term: Early-onset conductive, later mixed, hearing loss
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Speech delay was identified at age 18 months, and audiological evaluation showed both conductive and sensorineural hearing loss subsequently treated with a cochlear implant at age 3 years."
    explanation: >-
      Cochlear implantation for the hearing loss of a TNFRSF11A
      signal-peptide duplication; indirect because the child carried the
      allelic 12-bp allele rather than the FEO allele.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No improvement in hearing thresholds was obtained after reconstruction of the middle ear."
    explanation: >-
      Recorded as REFUTE of ossicular reconstruction as a route to hearing
      rehabilitation in FEO: middle-ear reconstruction did not improve
      thresholds where the ossicles were absent.
  - reference: PMID:15793411
    reference_title: "Hereditary bilateral conductive hearing loss caused by total loss of ossicles: a report of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common ossiculoplasty for improving the hearing thresholds in this condition may be unsuccessful; therefore, both surgeons and patients must be completely aware of the contingent undesirable results."
    explanation: >-
      The authors' warning, which is why implantation and amplification
      rather than ossiculoplasty are the rehabilitation route recorded here.
- name: Dental Surveillance and Prosthodontic Care
  description: >-
    Surveillance of the permanent dentition for external root resorption from
    childhood, preservation of teeth where feasible, prosthodontic
    replacement of lost teeth, and caution with orthodontic force and
    invasive dental surgery. Root resorption is often the presenting finding
    in a child and is a prognosticator of later bone disease; the
    recommendation that unexplained external root resorption should prompt
    genetic testing is recorded in the diagnosis section. Whether
    antiresorptive drugs slow root resorption is unproven; alendronate was
    proposed for that purpose in the allelic ESH family before the gene was
    known.
  treatment_term:
    preferred_term: dental surveillance and prosthodontic care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: External cervical and apical root resorption of permanent teeth
    term:
      id: HP:0006486
      label: Abnormal dental root morphology
  evidence:
  - reference: PMID:10509339
    reference_title: "Tooth root resorption associated with a familial bone dysplasia affecting mother and daughter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Conventional treatment strategies of root resorption offer only a poor prognosis for the dentition."
    explanation: >-
      The poor dental prognosis with conventional management, from the
      family later shown to have the allelic 15-bp duplication; indirect for
      that reason.
  - reference: PMID:10509339
    reference_title: "Tooth root resorption associated with a familial bone dysplasia affecting mother and daughter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Therapy using alendronate, a bisphosphonate compound and a potent inhibitor of osteoclastic activity, has reduced alkaline phosphatase levels, bone pain, and may offer an effective strategy to prevent tooth root resorption in this group of diseases."
    explanation: >-
      The proposal, not yet tested, that antiresorptive therapy might
      protect the dentition; indirect for the same reason.
prevalence:
- population: Worldwide, reported kindreds and cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists. In 2006 the disease had been observed
    world-wide in only three kinships and two unrelated American individuals;
    since then families or cases have been added from Spain, Iran, the Czech
    Republic, Australia and elsewhere, and the 2023 literature describes the
    TNFRSF11A duplication disorders collectively as ultra-rare. The Northern
    Irish kindred alone accounts for over 40 affected members across five
    generations.
  evidence:
  - reference: PMID:16470392
    reference_title: "Familial expansile osteolysis--not exclusively an adult disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial expansile osteolysis (FEO, MIM174810) is a rare syndrome which was observed world-wide in only three kinships and in two unrelated American individuals."
    explanation: >-
      The 2006 world count of known kindreds and cases.
  - reference: PMID:17447113
    reference_title: "Intragenic SNP haplotypes associated with 84dup18 mutation in TNFRSF11A in four FEO pedigrees suggest three independent origins for this mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 18-bp duplication in the first exon of the TNFRSF11A gene encoding RANK has been previously identified in four FEO pedigrees."
    explanation: >-
      Four molecularly confirmed pedigrees by 2007, before the Iranian
      family was added.
  - reference: PMID:36740137
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultra-rare mendelian osteolytic disorders caused by different length in-frame activating duplications within exon 1 of TNFRSF11A encoding receptor activator of nuclear factor-kappa B (RANK) comprise familial expansile osteolysis (FEO), expansile skeletal hyperphosphatasia (ESH), early-onset familial Paget's disease of bone (PDB2), juvenile Paget's disease 2 (JPD2), and panostotic expansile bone disease (PEBD)."
    explanation: >-
      The ultra-rare designation for the whole allelic series.
  - reference: PMID:3346299
    reference_title: "Familial expansile osteolysis. A new dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 40 cases in one family of an autosomal dominant bone dysplasia, which, though similar in some aspects to Paget's disease, seems unique in some features and in its natural history."
    explanation: >-
      The size of the founding kindred.
progression:
- phase: Early-onset hearing loss
  age_range: Childhood, sometimes as early as 4 years of age
  notes: >-
    Hearing loss is the earliest clinical manifestation, from resorption of
    the middle-ear ossicles, and precedes the skeletal lesions by years.
  evidence:
  - reference: PMID:2353208
    reference_title: "The radiographic features of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, hearing loss is the earliest manifestation of the disease, presenting sometimes as early as 4 years of age."
    explanation: >-
      The radiographic series of the original kindred places hearing loss
      first in the clinical sequence and gives the earliest recorded age.
- phase: External root resorption and premature tooth loss
  age_range: Childhood onward
  notes: >-
    Apical and cervical root resorption of the permanent teeth is the usual
    presenting finding in a child and leads to premature tooth loss. The
    cached abstract gives no age of onset for the dental phase; the
    paediatric case in the diagnosis section documents root resorption as
    the presenting finding.
  evidence:
  - reference: PMID:2353208
    reference_title: "The radiographic features of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Apical and cervical resorption of teeth is extremely common, resulting in premature loss of teeth."
    explanation: >-
      The same series records the dental phase and its outcome of premature
      tooth loss.
- phase: Progressive focal expansile osteolysis of the appendicular skeleton
  age_range: Early adulthood onward
  notes: >-
    Focal lytic lesions, most of them in the long bones, develop usually in
    early adulthood and enlarge progressively, expanding the bone and ending
    in fibrous and then fatty replacement of the medulla. The rates of
    lesion advance and the fracture counts reported in the full text of the
    radiographic series are not in the cached abstract and are not curated.
  evidence:
  - reference: PMID:10615125
    reference_title: "Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity."
    explanation: >-
      Places the onset of the focal osteolytic lesions in early adulthood and
      in the long bones.
  - reference: PMID:2353208
    reference_title: "The radiographic features of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Focal features comprise lytic areas which progressively enlarge, producing expansion of the bone and eventual disintegration due to fibrous and finally fatty replacement of the normal medulla."
    explanation: >-
      The progressive course of an individual lesion from lytic focus to
      expansion and medullary replacement.
  - reference: PMID:2353208
    reference_title: "The radiographic features of familial expansile osteolysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Almost 90% of these lesions occur in the appendicular skeleton."
    explanation: >-
      The appendicular predominance of the focal lesions.
animal_models:
- name: Tnfrsf11a 75dup27 heterozygous knock-in mouse
  species: Mouse
  genotype: Tnfrsf11a 75dup27 heterozygous (Tnfrsf11a75dup27/-)
  publication: PMID:33724536
  description: >-
    A knock-in mouse carrying the human 27-bp signal-peptide duplication that
    causes early-onset familial Paget disease of bone, the allelic disorder
    of FEO. Heterozygotes develop age-dependent focal osteolytic lesions of
    the hind limbs, and zoledronic acid prevents them. Marrow cells show
    impaired RANKL-induced osteoclast formation and signalling but increased
    osteoclast survival independent of RANKL. It is the only knock-in model
    of a TNFRSF11A signal-peptide duplication; no mouse carrying the FEO
    18-bp allele has been reported.
  modeled_mechanisms:
  - target: Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces age-dependent focal osteolytic lesions of the limb bones
      from a heterozygous signal-peptide duplication, which is the defining
      lesion of this node.
    limitations: >-
      The allele is the PDB2 27-bp duplication, not the FEO 18-bp one, so
      the model speaks to the shared signal-peptide mechanism rather than to
      FEO specifically; the human 27-bp phenotype is Paget-like with
      lytic-sclerotic lesions and jaw involvement rather than purely lytic,
      expansile limb disease. The lesions appear with age in a mouse, not
      from the second decade of a human life, and the abstract reports no
      hearing or dental phenotype.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Murine long bones and remodelling rates differ from human, and the
        mouse does not report the deafness and dental disease that precede
        skeletal disease in patients.
    readouts:
    - name: Focal osteolytic lesions of the hind limbs
      target: Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning
      direction: INCREASED
      interpretation: >-
        Age-dependent focal osteolysis in heterozygotes is the tissue-level
        correlate of the human lesion in this model.
      evidence:
      - reference: PMID:33724536
        reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling."
        explanation: >-
          Reports the focal osteolytic lesions that constitute this readout.
    - name: Lesion development under zoledronic acid
      target: Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning
      direction: ABOLISHED
      interpretation: >-
        Complete prevention of lesions by an osteoclast-targeted drug shows
        that the lesion is osteoclast-driven and drug-preventable in this
        model.
      evidence:
      - reference: PMID:33724536
        reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Treatment of these mice with zoledronic acid completely prevented the development of lesions."
        explanation: >-
          The prevention result behind this readout.
    evidence:
    - reference: PMID:33724536
      reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis, and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene, which encodes receptor activator of nuclear factor κB (RANK) protein."
      explanation: >-
        The authors' own framing of the model as informative for the whole
        family of signal-peptide duplication disorders, FEO included.
  - target: Constitutive Osteoclast Formation, Survival and Activation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Shows the heterozygous osteoclast phenotype: RANKL-driven formation is
      impaired, yet survival is prolonged without RANKL and lesions form in
      vivo, which is the paradox this node carries.
    limitations: >-
      Same allelic caveat as above. In addition, the model shows impaired
      rather than enhanced RANKL-induced osteoclast formation in marrow
      culture, so it recapitulates the survival component of the node and
      the in vivo outcome but not the increased differentiation the module
      target asserts.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse marrow osteoclastogenesis assays are a proxy for the human
        osteoclast lineage; no patient osteoclast data exist for comparison.
    readouts:
    - name: Osteoclast survival in the absence of RANKL
      target: Constitutive Osteoclast Formation, Survival and Activation
      direction: INCREASED
      interpretation: >-
        Prolonged osteoclast survival independent of ligand is the cellular
        signature of the mutant allele in this model.
      evidence:
      - reference: PMID:33724536
        reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Studies in vitro showed that RANK ligand (RANKL)-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a75dup27/- animals, but that osteoclast survival was increased independent of RANKL stimulation."
        explanation: >-
          Reports both the impaired formation recorded in the limitations
          and the increased survival that is this readout.
    evidence:
    - reference: PMID:33724536
      reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling."
      explanation: >-
        Supports treating the heterozygous model as informative for the
        osteoclast node.
- name: Tnfrsf11a 75dup27 homozygous knock-in mouse
  species: Mouse
  genotype: Tnfrsf11a 75dup27 homozygous (Tnfrsf11a75dup27/75dup27)
  publication: PMID:33724536
  description: >-
    The same allele in homozygous form. Rather than a more severe osteolytic
    disease, homozygotes have osteopetrosis at birth with complete absence
    of osteoclasts, and their marrow cells fail to form osteoclasts in
    response to RANKL and M-CSF. The result is curated because it is the
    single most informative negative finding about the mechanism: a
    receptor that was simply constitutively active would not abolish
    osteoclasts when present in two copies.
  modeled_mechanisms:
  - target: Constitutive Osteoclast Formation, Survival and Activation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Two copies of the mutant allele produce the opposite of the human
      disease at the osteoclast: no osteoclasts at all.
    limitations: >-
      No homozygous human exists, so the model tests a state the disease
      never occupies; its value is mechanistic, not phenotypic. It shows that
      the mutant receptor alone cannot drive osteoclastogenesis and that the
      human heterozygous phenotype depends on the co-presence of wild-type
      RANK, which is the content of the knowledge gap.
    evidence:
    - reference: PMID:33724536
      reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Surprisingly, Tnfrsf11a75dup27/75dup27 homozygotes had osteopetrosis at birth, with complete absence of osteoclasts."
      explanation: >-
        The homozygous osteopetrosis that is the failure to recapitulate.
    - reference: PMID:33724536
      reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and macrophage colony-stimulating factor (M-CSF) stimulation."
      explanation: >-
        The cellular basis: the mutant receptor alone cannot support
        osteoclast formation.
discussions:
- discussion_id: feo_constitutive_activation_versus_misprocessing
  prompt: >-
    Does the heterozygous TNFRSF11A signal-peptide duplication cause
    osteoclast overactivity through constitutive, ligand-independent
    NF-kappaB signalling by the mutant receptor, or through an effect of the
    misprocessed, ER-retained protein on the wild-type receptor or on the
    cell, such as an unfolded-protein response?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of RANK Signal-Peptide Cleavage and Endoplasmic Reticulum Retention
  - pathophysiology#Ligand-Independent RANK Signalling and NF-kappaB Activation
  rationale: >-
    The two positions are both in the literature and are not reconciled. The
    discovery study found increased NF-kappaB signalling from recombinant
    mutant RANK and called the mutations activating, and reviews still state
    the mechanism as ligand-independent NF-kappaB activation. The 2011 study
    found that constitutive activation occurred only with overexpression and
    of wild-type RANK as much as mutant, that at low expression the mutant
    receptor neither activated NF-kappaB constitutively nor responded to
    ligand, and that the mutant protein sits in the endoplasmic reticulum
    rather than at the membrane; it concluded that the disease cannot be
    explained by the mutant receptor alone. The knock-in mouse then showed
    that two mutant alleles abolish osteoclasts while one mutant allele
    beside a wild-type one prolongs osteoclast survival without RANKL, which
    is compatible with either a dominant effect of the misfolded protein on
    the cell or an interaction with wild-type receptor, and with neither
    simple model. Reviews have proposed an unfolded-protein-response route to
    NF-kappaB, which has not been tested in osteoclasts. The question matters
    for treatment: if signalling is truly ligand-independent, RANKL blockade
    should be ineffective, and the single denosumab response argues the other
    way. Every functional study to date has used the 27-bp or heterologous
    overexpression systems; no patient-derived osteoclast study of the 18-bp
    allele has been published.
  evidence:
  - reference: PMID:21472776
    reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results strongly suggest that the increased osteoclast formation/activity caused by these mutations cannot be explained by studying the homozygous phenotype alone but requires further detailed investigation of the heterozygous expression of the mutant RANK proteins."
    explanation: >-
      The authors' own statement of the gap: the heterozygous state, not the
      mutant receptor alone, holds the explanation.
  - reference: PMID:20458572
    reference_title: "New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Whole animal studies replicate the hyperactive osteoclast phenotype associated with these disorders and present only with heterozygous expression of the mutation, suggesting an as yet unexplained effect of the mutant allele on normal RANK function."
    explanation: >-
      A review names the unexplained effect of the mutant allele on normal
      RANK function as the open question. Evidence source is OTHER.
  - reference: PMID:33724536
    reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In homozygous form, however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation."
    explanation: >-
      The homozygous result that excludes a simply hyperactive receptor and
      keeps the gap open.
  proposed_experiments:
  - experiment_id: feo_patient_osteoclast_84dup18_signalling
    name: NF-kappaB and unfolded-protein-response signalling in heterozygous 84dup18 osteoclasts
    description: >-
      Differentiate osteoclasts from peripheral blood monocytes or
      iPSC-derived precursors of FEO patients carrying 84dup18, and from
      isogenic corrected controls, and measure basal and RANKL-stimulated
      NF-kappaB activity, osteoclast survival without RANKL, and
      unfolded-protein-response markers. A cell that shows basal NF-kappaB
      activity with UPR induction and no RANKL dose-response supports the
      misprocessing model; one that shows a shifted RANKL dose-response
      supports an interaction of mutant with wild-type receptor.
    would_support:
    - pathophysiology#Ligand-Independent RANK Signalling and NF-kappaB Activation
    supporting_outcome:
    - >-
      Basal NF-kappaB activity in heterozygous patient osteoclasts at
      endogenous expression levels, absent in isogenic controls.
    refuting_outcome:
    - >-
      No basal NF-kappaB activity, with prolonged survival explained by a
      pathway other than NF-kappaB.
  - experiment_id: feo_84dup18_knock_in_mouse
    name: Knock-in mouse carrying the FEO 18-bp duplication
    description: >-
      Generate a Tnfrsf11a 84dup18 knock-in and compare the heterozygous
      skeletal, ossicular and dental phenotype with the 75dup27 line, to
      test whether the length of the signal-peptide extension determines the
      lytic versus Paget-like pattern and whether the homozygous
      osteopetrosis is general to the allelic series.
- discussion_id: feo_denosumab_ligand_dependence
  prompt: >-
    Does RANKL blockade with denosumab control the osteoclast overactivity of
    FEO, and if so what does that say about the ligand dependence of
    signalling from the mutant receptor?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Denosumab
  - pathophysiology#Ligand-Independent RANK Signalling and NF-kappaB Activation
  rationale: >-
    The mechanism curated above is described as ligand-independent, and the
    ER-retained mutant receptor cannot be activated by ligand in vitro, which
    would predict that neutralising RANKL does little. Against that, one
    adult with FEO treated with denosumab in 2025 showed radiological
    improvement, better quality of life and enough control to permit limb
    salvage. A response to ligand blockade implies that osteoclast activity
    in FEO retains a RANKL-dependent component, most plausibly through the
    wild-type receptor in the same heterozygous cell. One case cannot settle
    it, and the knock-in mouse's osteoclasts survived without RANKL, which
    predicts a partial rather than complete response. The question is
    practical: bisphosphonates act on the osteoclast regardless of the
    receptor's state, denosumab does not.
  evidence:
  - reference: PMID:41264685
    reference_title: "A Novel Approach to the Treatment of Familial Expansile Osteolysis: A Rare Genetic Bone Pathology: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The use of denosumab for FEO displays improvement in radiological appearances of the affected bone, increased quality of life and may prevent the development of further lesions."
    explanation: >-
      The single response that raises the question.
  - reference: PMID:21472776
    reference_title: "Signal peptide mutations in RANK prevent downstream activation of NF-κB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In conclusion, signal peptide mutations lead to accumulation of RANK in the endoplasmic reticulum and prevent direct activation by RANK ligand."
    explanation: >-
      The in vitro finding that predicts ligand blockade should not act on
      the mutant receptor itself.
  proposed_experiments:
  - experiment_id: feo_denosumab_turnover_marker_series
    name: Prospective turnover-marker response to denosumab in FEO
    description: >-
      Treat a small series of adults with molecularly confirmed FEO with
      denosumab under a hypocalcaemia protocol and measure bone resorption
      markers and lesion scintigraphic activity before and after, comparing
      the depth of suppression with that achieved by zoledronic acid in the
      same patients. Complete suppression implies fully ligand-dependent
      osteoclast activity; partial suppression quantifies the
      ligand-independent component.
- discussion_id: feo_mouse_allele_mismatch
  prompt: >-
    How far does the Tnfrsf11a 75dup27 knock-in mouse, which carries the
    early-onset Paget allele, model the lytic, expansile, appendicular
    disease and the ossicular and dental resorption of the human 18-bp
    duplication?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Focal Expansile Osteolysis with Medullary Expansion and Cortical Thinning
  - pathophysiology#Middle-Ear Ossicular Resorption
  - pathophysiology#External Root Resorption of Permanent Teeth
  rationale: >-
    The model reproduces focal, age-dependent, drug-preventable osteolysis
    from a heterozygous signal-peptide duplication, which is strong evidence
    for the shared mechanism. What it does not do is carry the FEO allele:
    the 27-bp duplication produces a Paget-like lytic-sclerotic disease with
    jaw and skull involvement in humans, where the 18-bp duplication produces
    purely lytic limb lesions that end in fat-filled bone. Duplication length
    appears to matter to phenotype in the human allelic series, so an
    inference from one allele to another is an inference across the very
    variable that separates the disorders. The abstract reports no hearing or
    dental phenotype, so the two earliest human manifestations are unmodelled.
    This is recorded as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP
    because the model evidence exists and is good; what is open is its
    transfer to the specific human allele.
  evidence:
  - reference: PMID:33724536
    reference_title: "Insertion Mutation in Tnfrsf11a Causes a Paget's Disease-Like Phenotype in Heterozygous Mice and Osteopetrosis in Homozygous Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB."
    explanation: >-
      Identifies the allele modelled as the early-onset Paget one.
  - reference: PMID:12929927
    reference_title: "Phenotypic characterization of early onset Paget's disease of bone caused by a 27-bp duplication in the TNFRSF11A gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that the 75dup27 mutation of RANK causes a Paget's disease of bone-like phenotype that is distinct from, but which overlaps with, FEO and ESH."
    explanation: >-
      The human phenotype of the modelled allele is distinct from FEO, which
      is the substance of the mismatch.
  proposed_experiments:
  - experiment_id: feo_75dup27_mouse_ossicle_and_tooth_phenotyping
    name: Ossicular and dental phenotyping of the 75dup27 heterozygous mouse
    description: >-
      Micro-CT of the auditory ossicles and molar roots in heterozygous
      75dup27 mice across age, with auditory brainstem responses, to test
      whether the earliest human manifestations of the signal-peptide
      duplication are present in the existing model before an 18-bp line is
      made.

📚

References & Deep Research

References

7

PMID:10615125

Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis.

No top-level findings curated for this source.

PMID:21472776

Signal peptide mutations in RANK prevent downstream activation of NF-κB.

No top-level findings curated for this source.

PMID:30756140

Rare Inherited forms of Paget's Disease and Related Syndromes.

No top-level findings curated for this source.

PMID:3346299

Familial expansile osteolysis. A new dysplasia.

No top-level findings curated for this source.

PMID:11889411

Familial expansile osteolysis (excessive RANK effect) in a 5-generation American kindred.

No top-level findings curated for this source.

PMID:12362049

Familial expansile osteolysis in a large Spanish kindred resulting from an insertion mutation in the TNFRSF11A gene.

No top-level findings curated for this source.

PMID:8643278

Conductive hearing loss caused by hereditary incus necrosis: a study of familial expansile osteolysis.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Scope and lump/split decision. This entry is the 18-bp duplication disorder (84dup18 and the one-base-shifted equivalent) that carries the name familial expansile osteolysis and MONDO:0008275. The allelic TNFRSF11A signal-peptide disorders are described here but are not curated as subtypes: early-onset familial Paget disease of bone (PDB2, MONDO:0011183; 27-bp duplications 75dup27, 77dup27, 78dup27, 72dup27), expansile skeletal hyperphosphatasia (ESH; 15-bp duplication 84dup15; no MONDO term was found), juvenile Paget disease 2 (87dup15) and panostotic expansile bone disease (PEBD; 12-bp duplication). They share the molecular lesion, the deafness and the tooth loss, and differ in the skeletal pattern: ESH has hyperostotic widening of the long bones with painful phalangeal lesions and episodic hypercalcaemia rather than large cortical-thinning osteolytic lesions; PDB2 has a Paget-like lytic-sclerotic picture with striking jaw and skull involvement; PEBD has panostotic disease with massive jaw tumours. Evidence from these allelic disorders is used here only where it bears on the shared mechanism or on the treatment class, and is marked directness INDIRECT when it does. Juvenile Paget disease (TNFRSF11B, osteoprotegerin loss) and classic Paget disease of bone (SQSTM1 and others; see Paget_Disease_of_Bone) are different genes and different entries; both are cross-referenced because the middle of the causal chain, unrestrained RANK signalling into osteoclasts, is common to all of them. Module conformance. Two nodes conform to osteoporosis_bone_resorption. The osteoclast node conforms to RANKL-Driven Osteoclastogenesis with the disorder-specific substitution that the module's driver, a raised RANKL/OPG ratio, is replaced here by a constitutively mis-signalling RANK receptor; the ligand is not in excess, the receptor is out of ligand control. The focal osteolysis node conforms to Increased Osteoclastic Bone Resorption. The entry deliberately does not conform to the module's Impaired Osteoblastic Bone Formation node, because FEO is a high-turnover disease in which osteoblast activity is increased alongside osteoclast activity rather than deficient; the bone is lost because resorption outruns a formation arm that is itself working hard, not because formation has failed. Animal model. No mouse carrying the FEO 18-bp duplication has been reported. The only knock-in model of a TNFRSF11A signal-peptide duplication carries the PDB2 allele 75dup27, and it is curated as a partial model with that caveat. Earlier whole-animal work referred to in reviews is not curated because the primary reports with quotable methods were not found. Provenance. Built from an Edison (Falcon) deep-research report, research/Familial_Expansile_Osteolysis-deep-research-falcon.md, which passed the Named-Entity-Confusion preflight against MONDO:0008275. Falcon cites by DOI and by corpus key; every source used here was resolved to its PubMed record and quoted from the cached abstract, and the primary papers the report did not carry (the 1988 and 1989 Northern Irish descriptions, the 1990 dental studies, the 1994 linkage paper, the 2003 and 2007 mutation papers, the 2005 ossicle study and the 2025 denosumab case) were found through PubMed directly. Three papers the brief asked for, the 2002 American kindred description in Medicine, the 2002 Spanish kindred paper and the 1996 incus necrosis study, have no abstract in PubMed and are listed as references without quoted evidence. The Schafer 2014 paper named in the brief as a denosumab report is the panostotic expansile bone disease case and describes alendronate and pamidronate, not denosumab; it is cited for what it says. No GeneReviews chapter exists for this disorder.

Create: Familial Expansile Osteolysis (MONDO:0008275) · 2026-09-18T14:28:15Z · View source

New entry curated from the Edison Falcon deep-research report research/Familial_Expansile_Osteolysis-deep-research-falcon.md with report DOIs resolved to PMIDs through PubMed and all snippets quoted from cached abstracts; the report's one unresolved DOI was not cited. No GeneReviews chapter exists. Eight-node pathograph: TNFRSF11A exon 1 signal-peptide tandem duplication, failure of RANK signal-peptide cleavage with endoplasmic reticulum retention, ligand-independent RANK signalling and NF-kappaB activation (modifier GAIN_OF_FUNCTION, the qualitative outside-regulatory-control case), constitutive osteoclast formation, survival and activation, generalized accelerated bone remodelling, focal expansile osteolysis with medullary expansion and cortical thinning, middle-ear ossicular resorption, and external root resorption of permanent teeth. Lump/split: the 18-bp duplication disorder only; the allelic TNFRSF11A signal-peptide disorders (early-onset familial Paget disease of bone PDB2, expansile skeletal hyperphosphatasia, juvenile Paget disease 2, panostotic expansile bone disease) are described in notes and the genetic block and their evidence is used only where it bears on the shared mechanism, marked directness INDIRECT. Juvenile Paget disease (TNFRSF11B) and classic Paget disease of bone (SQSTM1) are cross-referenced as different genes. Two nodes conform to osteoporosis_bone_resorption with the substitution that a constitutively mis-signalling RANK receptor replaces a raised RANKL/OPG ratio as the driver. The unresolved question whether the phenotype arises from membrane gain-of-function or from misfolded-protein accumulation (Hughes 2000 versus Crockett 2011) is recorded as a KNOWLEDGE_GAP. Biochemical block covers alkaline phosphatase and bone turnover markers; treatments cover bisphosphonates, denosumab, surgical stabilisation, hearing and dental management. Validated: just validate passed; count-verified-snippets 121/121; validate-terms, check-entity-refs, check-causal-targets, check-enum-values and check-duplicate-keys passed; pytest -k Familial_Expansile_Osteolysis passed. A first attempt at this curation was cut off by a session limit before writing; this record describes the completed second pass.

Falcon ▸

Familial Expansile Osteolysis: Disease-Characteristics Report

Edison Scientific Literature 41 citations 2026-09-04T23:36:53.306540

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)

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.	(whyte2004heritabledisordersof pages 1-2, whyte2004heritabledisordersofa pages 1-2, ralston2019rareinheritedforms pages 1-3)
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. Other exon-1 duplications produce overlapping RANK-associated phenotypes.	(whyte2004heritabledisordersof pages 1-2, ralston2019rareinheritedforms pages 3-4, whyte2014juvenilepagetsdisease pages 14-15)
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.	(crone1990theradiographicfeatures pages 1-2, whyte2004heritabledisordersof pages 2-3, whyte2004heritabledisordersof pages 14-14, craven2023earlyidentificationof pages 3-4)
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.	(marik2006familialexpansileosteolysis—not pages 1-3, crone1990theradiographicfeatures pages 1-2, whyte2004heritabledisordersofa pages 2-3, whyte2006pagetsdiseaseof pages 4-6)
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.	(ralston2019rareinheritedforms pages 3-4, crone1990theradiographicfeatures pages 2-5, crone1990theradiographicfeatures pages 1-2, marik2006familialexpansileosteolysis—not pages 3-4)
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.	(marik2006familialexpansileosteolysis—not pages 1-3, crone1990theradiographicfeatures pages 2-5, craven2023earlyidentificationof pages 1-3)
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.	(alonso2021insertionmutationin pages 9-9, ralston2019rareinheritedforms pages 4-6, ralston2019rareinheritedforms pages 3-4, ralston2019rareinheritedforms pages 20-25)
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.	(whyte2006pagetsdiseaseof pages 6-10, craven2023earlyidentificationof pages 3-4, whyte2002familialexpansileosteolysis pages 13-15, craven2023earlyidentificationof pages 1-3)
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; Craven et al., DOI.	(whyte2006pagetsdiseaseof pages 6-10, craven2023earlyidentificationof pages 3-4, whyte2002familialexpansileosteolysis pages 13-15, craven2023earlyidentificationof pages 1-3)
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.	(marik2006familialexpansileosteolysis—not pages 1-3, whyte2006pagetsdiseaseof pages 6-10, ralston2019rareinheritedforms pages 1-3)

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

Phenotype	Characteristics and frequency	Suggested HPO term
Hearing loss	Often earliest feature; reported as early as age 4 and usually in the first or second decade. Initially conductive, later mixed sensorineural. Approximately 95% in the classic Northern Ireland family. Fibrous replacement/necrosis of the incus is characteristic.	Hearing impairment HP:0000365; conductive hearing impairment HP:0000405; sensorineural hearing impairment HP:0000407
External tooth-root resorption	Permanent teeth show cervical/apical external resorption, mobility, fracture, pain, and premature loss, often beginning in adolescence; deciduous teeth generally spared. Dental abnormalities occurred in approximately 94% of screened classic-kindred patients.	Abnormality of dental root; premature loss of teeth HP:0006480
Focal expansile osteolysis	Usually begins at 15–45 years, although childhood onset and fracture at age 5 are documented. Progressive lysis, cortical thinning, expansion, deformity, and mechanical failure; variable severity.	Osteolysis HP:0002797; abnormal bone structure HP:0011842
Bone pain	Typically localized to active lesions; reported onset 18–44 years in the classic series.	Bone pain HP:0002653
Pathological fracture	Twelve fractures among 97 lesions (12.4%); fractures generally united normally.	Pathologic fracture HP:0002756
Limb deformity/bowing	Progressive, particularly tibial bowing and S-shaped deformity; expansion can reach 3.5 times normal diameter.	Bowing of the long bones HP:0006487
Osteopenia/osteoporosis	Generalized low mass and coarse or “fish-net” trabeculation, particularly in the American phenotype.	Osteopenia HP:0000938; osteoporosis HP:0000939
High bone turnover	Elevated ALP and urinary hydroxyproline; bone ALP, osteocalcin, TRAP, deoxypyridinoline, or N-telopeptide may also be high. Calcium, phosphate, and PTH are usually normal before treatment.	Elevated circulating alkaline phosphatase HP:0003155

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

A heterozygous exon-1 TNFRSF11A in-frame duplication leads to elongation of the RANK signal peptide.
Signal-peptide alteration results in defective cleavage and impaired trafficking of mutant RANK to the plasma membrane.
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)
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)
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)
Osteoclast dysregulation leads to excessive focal resorption and coupled high-turnover remodeling, reflected by elevated ALP/resorption markers and avid scintigraphic uptake.
Persistent resorption exceeding effective replacement results in trabecular and cortical loss, marrow fibrosis/vascularity, expansion, and eventual fatty replacement.
Structural failure leads to pain, bowing, deformity, and pathological fractures.
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

Recognize the combination of early hearing loss, permanent-tooth external root resorption, elevated turnover, and appendicular expansile osteolysis.
Measure serum total/bone-specific ALP, calcium, phosphate, creatinine, PTH, and 25-hydroxyvitamin D; consider osteocalcin and serum/urine resorption markers.
Obtain targeted radiographs and whole-body technetium bone scintigraphy; use DXA to quantify generalized low bone mass.
Perform panoramic dental imaging or CBCT and formal audiology; temporal-bone CT/MRI may define ossicular/inner-ear pathology.
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

(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.
(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.
(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.
(whyte2004heritabledisordersof pages 14-14): MP Whyte and S Mumm. Heritable disorders of the rankl/opg/rank signaling pathway. Unknown journal, 2004.
(whyte2004heritabledisordersof pages 1-2): MP Whyte and S Mumm. Heritable disorders of the rankl/opg/rank signaling pathway. Unknown journal, 2004.
(whyte2004heritabledisordersofa pages 1-2): MP Whyte and S Mumm. Heritable disorders of the rankl/opg/rank signaling pathway. Unknown journal, 2004.
(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.
(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.
(whyte2004heritabledisordersof pages 2-3): MP Whyte and S Mumm. Heritable disorders of the rankl/opg/rank signaling pathway. Unknown journal, 2004.
(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.
(whyte2004heritabledisordersofa pages 2-3): MP Whyte and S Mumm. Heritable disorders of the rankl/opg/rank signaling pathway. Unknown journal, 2004.
(whyte2006pagetsdiseaseof pages 4-6): 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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(craven2023earlyidentificationof pages 6-8): 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.
(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.
(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

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	10
Unresolved (possible confabulation)	1
Unverifiable	0
References weighed for topical relevance	10
On topic	3
Off topic	0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

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

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	21
Resolved	21
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0

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

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Familial Expansile Osteolysis: Disease-Characteristics Report

Executive summary

1. Disease information

2. Etiology, risk, and protective factors

Causal factor

Risk factors and modifiers

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Recommended approach

11. Outcome and prognosis

12. Treatment and real-world implementation

Antiresorptives

Hearing, dental, orthopedic, and supportive care

13. Prevention

14. Other species and natural disease

15. Model organisms

Evidence appraisal and research gaps

Artifacts

Reference Validation

Unresolved references

Term Validation