Otosclerosis

Complex MONDO:0005349 Pathograph 24 Show in embeddings browser Disorder of the Middle Ear Metabolic Bone Disease

Otosclerosis is a bone dystrophy confined to the otic capsule — the endochondral bone shell of the inner ear, which in health is one of the least remodeled bones in the body. In otosclerosis that quiescence is lost focally: osteoclasts resorb endochondral bone at discrete foci, most often at the fissula ante fenestram just anterior to the oval window, and osteoblasts then replace the resorbed bone with disorganized, poorly organized new bone. The active, hypervascular resorptive phase is called otospongiosis; the inactive, densely mineralized end state is otosclerosis proper, and both appear in the same temporal bone. The lesion causes disease by where it sits rather than by how much bone it destroys. A focus that reaches the annular ligament ankyloses the stapes footplate in the oval window, and sound can no longer be transmitted through the ossicular chain — progressive conductive hearing loss, typically beginning in the third decade and bilateral in most patients. Medial extension to the cochlear endosteum adds a sensorineural component, giving mixed hearing loss. Two features frame the etiology. Around half of patients have an affected relative, and the familial pattern is autosomal dominant with reduced penetrance, but two decades of linkage mapping produced ten OTSC intervals and almost no genes; a 2023 three-biobank GWAS instead found 27 common risk loci and confirmed a polygenic architecture, with the nearest genes clustering on bone remodeling, mineralization and TGF-beta signalling. And the disease is disappearing: US population incidence fell from 18.5 per 100,000 person-years in the early 1970s to 3.2 by 2015-2017, a decline widely — but not conclusively — attributed to measles vaccination, since measles virus RNA has been recovered from otosclerotic stapes in some series and not at all in others.

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1
Mappings
2
Inheritance
8
Pathophys.
3
Histopath.
7
Phenotypes
24
Pathograph
10
Genes
5
Medical Actions
2
Differentials
1
Models
1
Deep Research
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Classifications

Harrison's Part
DISORDER OF EAR GENETICS ENVIRONMENT DISEASE
🔗

Mappings

ICD-10-CM
ICD10CM:H80 Otosclerosis
skos:exactMatch ICD-10-CM
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Inheritance

2
Autosomal dominant with reduced penetrance (familial otosclerosis) HP:0000006
Around half to sixty per cent of patients have an affected relative, and in most such families transmission fits autosomal dominance with incomplete penetrance. The FOXL1 and SMARCA4 kindreds are the two families in which a segregating dominant variant has actually been identified.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"In most families, the inheritance pattern is autosomal dominant with incomplete penetrance."
States both the mode and the reduced penetrance recorded here.
Polygenic susceptibility (non-familial otosclerosis) HP:0010982
Sporadic disease behaves as a complex trait. A three-biobank GWAS meta-analysis of 3,504 cases and 861,198 controls found 27 genome-wide-significant loci and SNP-based heritability estimates of 0.15-0.27, confirming a polygenic architecture rather than a few high-impact genes.
Polygenic inheritance
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"We confirm a polygenic basis to otosclerosis."
The GWAS authors state the polygenic conclusion this record encodes.
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Pathophysiology

8
Reduced Osteoprotegerin Restraint of Osteoclastogenesis
In health the otic capsule is protected from remodeling by osteoprotegerin, secreted in large amounts by the spiral ligament, which acts as a decoy receptor for RANKL and suppresses osteoclast recruitment and activation. Osteoprotegerin transcript is significantly reduced in otosclerotic stapes footplates relative to normal stapes, releasing that restraint.
TNFRSF11B hgnc:11909 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNFRSF11B (hgnc:11909). hgnc:11909 is a gene from the HUGO Gene Nomenclature Committee.
negative regulation of osteoclast differentiation GO:0045671 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of osteoclast differentiation (GO:0045671). GO:0045671 is a biological process from the Gene Ontology. ↓ DECREASED
bony otic capsule UBERON:0005411 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bony otic capsule (UBERON:0005411). UBERON:0005411 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Loss of Otic Capsule Remodeling Quiescence Withdrawal of osteoprotegerin's decoy-receptor restraint permits RANKL-driven osteoclast recruitment in a bone that is otherwise not remodeled.
Show evidence (2 references)
PMID:37647735 SUPPORT Human Clinical
"This is explained by the presence of OPG, a mediator produced in large quantities by the spiral ligament that inhibits the recruitment, formation, and activation of osteoclasts."
States the osteoprotegerin mechanism that normally holds otic-capsule remodeling in check.
PMID:24676726 SUPPORT Human Clinical
"The OPG expression level was significantly lower in otosclerotic tissues comparing to controls."
Measures the loss of that restraint directly in otosclerotic stapes versus cadaveric control stapes.
Local Proinflammatory Cytokine Expression in the Otosclerotic Focus
Otosclerotic footplates express TNF-alpha and IL-1beta transcripts at levels significantly above normal stapes, marking the focus as an inflammatory lesion and supplying two of the classical osteoclast-activating cytokines.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Focal Otospongiotic Bone Resorption TNF-alpha and IL-1beta are osteoclast-activating cytokines; their presence in the focus alongside absent osteoprotegerin is read by the source as the signature of active bone remodeling in the stapes.
Show evidence (1 reference)
PMID:24676726 SUPPORT Human Clinical
"The transcript level of TNF-α and IL-1β was significantly higher in otosclerotic tissues comparing to normal tissue."
Directly measures the elevated cytokine transcripts in surgically removed otosclerotic stapes.
Dysregulated TGF-beta Signaling in the Otic Capsule
TGF-beta1 regulates both osteoblast and osteoclast lineages and is produced within the otic capsule and by inner-ear tissues from which it can diffuse. An intronic TGFB1 variant is genome-wide significant for otosclerosis, and several further risk loci (SMAD3, CD109, LTBP3, AHSG, and a haplotype overlapping RUNX2) lie on the same pathway, making TGF-beta signalling the most consistently implicated molecular axis.
TGFB1 hgnc:11766 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TGFB1 (hgnc:11766). hgnc:11766 is a gene from the HUGO Gene Nomenclature Committee. SMAD3 hgnc:6769 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SMAD3 (hgnc:6769). hgnc:6769 is a gene from the HUGO Gene Nomenclature Committee. CD109 hgnc:21685 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CD109 (hgnc:21685). hgnc:21685 is a gene from the HUGO Gene Nomenclature Committee. LTBP3 hgnc:6716 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LTBP3 (hgnc:6716). hgnc:6716 is a gene from the HUGO Gene Nomenclature Committee. AHSG hgnc:349 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AHSG (hgnc:349). hgnc:349 is a gene from the HUGO Gene Nomenclature Committee.
transforming growth factor beta receptor signaling pathway GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Loss of Otic Capsule Remodeling Quiescence TGF-beta1 is proposed to reach the otic capsule paracrine from inner-ear tissue and regulate its remodeling; the step from altered signalling to loss of quiescence is inferred from the genetics rather than demonstrated in human otic capsule.
Show evidence (2 references)
PMID:36653343 SUPPORT Human Clinical
"We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies."
The GWAS meta-analysis itself identifies TGF-beta signalling as the recurring pathway across its risk loci.
PMID:36653343 SUPPORT Human Clinical
"Other genes relevant for TGFβ signalling include SMAD3, CD109, LTBP3, and AHSG, all of which are nearest to the lead variants in their respective loci, and RUNX2 which partly overlaps an association signal"
Names the specific pathway members behind this node's gene list.
Loss of Otic Capsule Remodeling Quiescence
The mature otic capsule is a near-static bone: osteoblast and osteoclast activity is almost absent, and turnover runs at roughly 0.13% per year against about 10% in ordinary skeletal bone. In otosclerosis both lineages are reactivated at focal sites, most plausibly at the residual islands of immature cartilage (globuli interossei) retained in the human capsule.
osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology. osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
bone remodeling GO:0046849 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bone remodeling (GO:0046849). GO:0046849 is a biological process from the Gene Ontology. ↑ INCREASED
bony otic capsule UBERON:0005411 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bony otic capsule (UBERON:0005411). UBERON:0005411 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Focal Otospongiotic Bone Resorption Reactivation of osteoclasts within the capsule is the first half of the remodeling cycle that produces the otosclerotic focus.
Show evidence (2 references)
PMID:37399313 SUPPORT Human Clinical
"under normal conditions, osteoblast and osteoclast activity of bone turnover is almost entirely absent in the mature otic capsule"
Establishes the baseline quiescence whose loss defines this node.
PMID:37647735 SUPPORT Human Clinical
"The otic capsule contains regions of immature cartilage called globuli interossei, which may correspond to the earliest loci of otosclerosis."
Identifies the candidate cellular substrate where quiescence is first lost.
Focal Otospongiotic Bone Resorption
The active phase. Bone is resorbed around vessels and replaced by fibrous connective tissue, the perivascular spaces enlarge into vascular channels, and the focus becomes hypervascular and hypercellular with osteoclastic giant cells. The commonest site is the fissula ante fenestram immediately anterior to the oval window. While active the lesion is termed otospongiosis.
multinuclear osteoclast CL:0000779 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves multinuclear osteoclast (CL:0000779). CL:0000779 is a cell type from the Cell Ontology.
bone resorption GO:0045453 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bone resorption (GO:0045453). GO:0045453 is a biological process from the Gene Ontology. ↑ INCREASED
bony otic capsule UBERON:0005411 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bony otic capsule (UBERON:0005411), qualified as extent focal. UBERON:0005411 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sclerotic Bone Replacement of the Focus Within the resorbed space reticular cells and fibroblasts take on osteoblast form, matrix calcification begins, and immature bone is laid down — the resorptive phase converting into the sclerotic one.
Schwartze Sign Anastomoses between the hypervascular active focus and submucosal vessels of the cochlear promontory produce the promontory hyperemia visible through the tympanic membrane.
Show evidence (2 references)
PMID:37647735 SUPPORT Human Clinical
"Otosclerosis only affects the temporal bone, particularly the fissula ante fenestram, but may extend to the region of the labyrinth and cochlea, oval window, and round window."
Establishes the focal site of onset and the routes of extension.
PMID:37647735 SUPPORT Human Clinical
"Bone is resorbed around a vessel and replaced by a fibrous connective tissue. These areas of active disease are characterized by the presence of osteoclastic giant cells and vascular proliferation."
Describes the resorptive, hypervascular tissue architecture of the active focus.
Sclerotic Bone Replacement of the Focus
Osteoblasts replace the resorbed bone with dense, disorganized, poorly organized new bone that does not respect the normal contours of the labyrinth or ossicles and may become exophytic into the middle ear and perilymphatic space. In this inactive state the lesion is termed otosclerosis proper.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
bone mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bone mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ↑ INCREASED ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Stapes Footplate Fixation Expansion of the focus at the anterior oval window ankyloses the adjacent stapes footplate.
Cochlear Endosteal Involvement Medial rather than lateral progression of the same focus carries the lesion to the cochlear endosteum.
Show evidence (2 references)
PMID:37647735 SUPPORT Human Clinical
"Depending on whether the disease is active or inactive, it is termed otospongiosis (active) or otosclerosis (inactive)."
Establishes the two-phase naming this node and its upstream node represent.
PMID:37647735 SUPPORT Human Clinical
"The otosclerotic process does not respect the normal limits and contours of the labyrinth or ossicles and may become exophytic and extend into the middle ear and perilymphatic space."
Describes the disorganized expansion of the sclerotic focus beyond normal bone boundaries.
Stapes Footplate Fixation
Otosclerotic bone bridging the stapediovestibular joint ankyloses the footplate within the oval window. The ossicular chain can no longer transfer tympanic vibration to the perilymph, and an air-bone gap appears on audiometry.
stapes base UBERON:0002496 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in stapes base (UBERON:0002496). UBERON:0002496 is an anatomical location from the Uberon multi-species anatomy ontology. oval window UBERON:0002501 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in oval window (UBERON:0002501). UBERON:0002501 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive Conductive Hearing Loss
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"In classic otosclerosis, the conduction of sound through the ossicular chain is impeded due to fixation of the stapes footplate by pathologic bone remodeling, leading to conductive hearing loss."
States the mechanical consequence of footplate fixation that defines this node.
Cochlear Endosteal Involvement
Medial extension of the focus into the cochlear endosteum damages intracochlear structures and adds a sensorineural component. Reported rates differ by series and by whether the criterion is histologic involvement or measured sensorineural loss: up to 10% of cases by one account, 20-30% by another. Involvement of the spiral ligament and of the saccular neuroepithelium is the proposed basis for the vestibular symptoms that accompany endosteal disease.
cochlea UBERON:0001844 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cochlea (UBERON:0001844). UBERON:0001844 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sensorineural Hearing Loss
Mixed Hearing Loss
Vestibular Symptoms Saccular type I hair-cell loss is seen only when endosteal involvement is present; the intervening step (toxic metabolites released into inner-ear fluids, or endolymphatic hydrops) is not settled.
Show evidence (2 references)
PMID:36653343 SUPPORT Human Clinical
"When bone remodeling progresses to involve the cochlear endosteum, otosclerosis can cause additional sensorineural hearing loss in 20–30% of patients, which reflects damage to the delicate intracochlear cells."
States both the anatomical step and the sensorineural consequence.
PMID:37399313 SUPPORT Human Clinical
"in up to 10% of cases otosclerotic foci involve the cochlear endosteum that may also manifest as sensorineural or mixed hearing loss"
Cited alongside the 20-30% figure because the two sources disagree; recorded so the disagreement is visible rather than resolved by picking one number.
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Histopathology

3
Otospongiotic (Active) Focus with Vascular Proliferation
Enlarged perivascular spaces, bone resorbed around vessels and replaced by fibrous tissue, osteoclastic giant cells and vascular proliferation. Osteoblast and osteoclast precursors, histiocytes and macrophages are seen on electron microscopy.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"These areas of active disease are characterized by the presence of osteoclastic giant cells and vascular proliferation."
States the two defining histologic features of the active focus.
Sclerotic (Inactive) Focus of Dense Mineralized Bone
The burnt-out end state of the lesion: dense mineralized bone replacing the resorbed otic-capsule bone.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"The otosclerosis focus may appear as dense mineralized bone (sclerosis) or active, well-vascularized bone (spongiotic)."
Names both the sclerotic and spongiotic appearances of the focus.
Blue Mantles
Basophilic (bluish on H&E) zones of recently remodeled bone bordering the focus, among the earliest histologic manifestations. No NCIT or HP term names this finding, so the descriptor is free text.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"One of the first histologic manifestations of otosclerosis is known as blue mantles, which are basophilic staining regions visualized after application of Hematoxylin and Eosin (H&E)."
Defines the finding and marks it as an early manifestation.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Otosclerosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Ear 5
Progressive Conductive Hearing Loss Progressive conductive hearing impairment HP:0008607 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive conductive hearing impairment (HP:0008607), qualified as course progressive. HP:0008607 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Sequelae: Paracusis of Willis
Show evidence (2 references)
PMID:37647735 SUPPORT Human Clinical
"The classic presentation of otosclerosis consists of progressive conductive hearing loss in adulthood."
States the phenotype and its course directly.
PMID:36653343 SUPPORT Human Clinical
"Initial manifestation is often limited to one ear, but eventual bilateral disease is observed in 70–80% of cases"
Supports the laterality course described for this phenotype.
Mixed Hearing Loss Mixed hearing impairment HP:0000410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mixed hearing impairment (HP:0000410). HP:0000410 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37399313 SUPPORT Human Clinical
"in up to 10% of cases otosclerotic foci involve the cochlear endosteum that may also manifest as sensorineural or mixed hearing loss"
Names mixed hearing loss as a manifestation of endosteal involvement.
Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34633540 SUPPORT Human Clinical
"Patients typically present with conductive HL which often progresses to mixed loss (cochlear otosclerosis); purely sensorineural hearing loss (SNHL) is rare."
Establishes both that pure sensorineural loss occurs and that it is the uncommon presentation.
Tinnitus FREQUENT HP:0000360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tinnitus (HP:0000360). HP:0000360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"Tinnitus is a highly prevalent symptom."
Supports both the phenotype and the FREQUENT band; the source gives a qualitative "highly prevalent" rather than a percentage, which maps to FREQUENT.
Vestibular Symptoms Abnormal vestibular function HP:0001751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vestibular symptoms, annotated with Abnormal vestibular function (HP:0001751). HP:0001751 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"Vestibular symptoms have been reported in up to 40% of patients with otosclerosis."
Supports the phenotype and the upper bound quoted in the description.
Other 2
Paracusis of Willis
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"Patients may describe improved hearing clarity in noisy environments."
Describes the symptom this phenotype records.
Schwartze Sign
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"This sign is inconsistently found in patients with otosclerosis and is not necessary for diagnosis."
Supports the caveat that makes this an unreliable but real sign.
🧬

Genetic Associations

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OTSC linkage loci (OTSC1-OTSC10) (Two decades of linkage mapping in multiplex families defined ten autosomal dominant OTSC intervals (OTSC1 15q25-qter, OTSC2 7q34-q36, OTSC3 6p22.3-p21.3, OTSC4 16q22.1-q23.1, OTSC5 3q22-q24, OTSC7 6q13-q16.1, OTSC8 9p13.1-q21.11, OTSC10 1q41-q44; OTSC6 and OTSC9 unpublished). The intervals are large — 10 to 34 Mb — and, apart from FOXL1 mapping into the 16q24.1 region, none has yielded a causal gene. These loci are recorded here as genetic detail of one disease, not as clinical subtypes.)
relationship_type: UNKNOWN
Show evidence (2 references)
PMID:34633540 SUPPORT Human Clinical
"multiplex families have been used to map ten autosomal dominant (OTSC) loci to large genomic intervals"
Establishes the number and nature of the OTSC intervals recorded here.
PMID:36653343 SUPPORT Human Clinical
"However, efforts to identify causative genes have produced inconsistent results, with insufficient evidence for most candidate genes"
Supports the statement that the intervals have largely not yielded causal genes.
FOXL1 (A 15 bp coding deletion (rs764026385) in the C-terminus of FOXL1 co-segregates with autosomal dominant otosclerosis in a large Newfoundland family of English extraction and was found in a second unrelated case on a shared haplotype. The mutant protein is transcribed, translated and correctly nuclear, but loses its C-terminal alpha helix and all transcriptional activity, implying that wild-type FOXL1 normally restrains otic-capsule bone remodeling.)
Gene: FOXL1 hgnc:3817 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FOXL1 (hgnc:3817). hgnc:3817 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:34633540 SUPPORT Human Clinical
"we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family"
Reports the co-segregating variant that makes this a causative gene claim.
PMID:34633540 SUPPORT In Vitro
"However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure."
The functional consequence was measured in reporter assays rather than in patients, so it is graded IN_VITRO separately from the segregation evidence above.
SMARCA4 (Whole-exome sequencing plus linkage in a kindred with seven affected individuals identified a disease-causing SMARCA4 variant (p.E1548K), encoding a component of the PBAF chromatin-remodeling complex. Knock-in mice carrying the orthologous change are the only animal model that reproduces an otosclerosis-like phenotype.)
Gene: SMARCA4 hgnc:11100 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SMARCA4 (hgnc:11100). hgnc:11100 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:37399313 SUPPORT Human Clinical
"Through genetic studies of kindred with seven individuals affected by apparent autosomal dominant otosclerosis, we identified a disease-causing variant in SMARCA4, encoding a key component of the PBAF chromatin remodelling complex."
Reports the human genetic finding behind this CAUSATIVE assignment.
MEPE (MEPE encodes matrix extracellular phosphoglycoprotein, an osteocyte product with roles in both mineralization and osteoclast regulation. A rare frameshift variant (rs753138805), enriched in Finns, carries by far the largest effect of any otosclerosis allele reported to date and fine-maps as the most likely causal variant at its locus. MEPE protein is present in maturing and adult mouse otic capsule osteocytes.)
Gene: MEPE hgnc:13361 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MEPE (hgnc:13361). hgnc:13361 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:36653343 SUPPORT Human Clinical
"In the chromosome 4 locus near the MEPE gene, the rare frameshift variant rs753138805 (EAF 0.3% in controls and 1.3% in cases) was the lead variant in the GWAS in FinnGen with an odds ratio of 21.5 (95% CI 9.6-48.4)"
Gives the specific variant and effect size behind this susceptibility claim.
PMID:36653343 SUPPORT Model Organism
"Our localization of MEPE protein within the maturing and adult otic capsule validates our GWAS finding."
The expression validation was done by immunostaining mouse cochleae, so it is graded MODEL_ORGANISM separately from the human association above.
TGFB1 (The most consistently replicated common susceptibility gene. An intronic variant (rs8105161) reached genome-wide significance in the three-biobank meta-analysis, and a British case-control study independently associated the coding variant rs1800472, most strongly among non-familial cases.)
Gene: TGFB1 hgnc:11766 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TGFB1 (hgnc:11766). hgnc:11766 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:36653343 SUPPORT Human Clinical
"the only genome-wide significant association observed for the intronic TGFB1 variant rs8105161"
Gives the genome-wide-significant TGFB1 association.
PMID:29728750 SUPPORT Human Clinical
"Evidence of an association between rs1800472 in TGFB1 and otosclerosis was found (p = 0.034), this association was strongest amongst non-familial cases (p = 0.011)."
Independent replication in a different cohort, and locates the effect in non-familial disease.
RELN (Reelin was the first otosclerosis GWAS hit and remains associated in the largest meta-analysis, but replication has been erratic and a British study found the signal only in familial cases. Reelin has no known role in bone biology, which the field has repeatedly noted as a puzzle rather than a mechanism.)
Gene: RELN hgnc:9957 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RELN (hgnc:9957). hgnc:9957 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (2 references)
PMID:36653343 SUPPORT Human Clinical
"In the locus on chromosome 7, the strongest association was observed for variants in the second and third introns of RELN concordant with previous GWAS"
Confirms the RELN association in the largest available meta-analysis.
PMID:29728750 SUPPORT INDIRECT Human Clinical
"However, a significant association (p = 0.0057) was detected between one RELN SNP (rs39399) and otosclerosis in familial patients."
Supports a RELN association only in the familial stratum; the same study found none in the whole cohort, so it bears on the claim through a subgroup analysis.
CD109 (A GWAS lead variant in an intron of CD109 falls inside the previously mapped OTSC7 linkage region on 6q13-16.1, which is the only OTSC interval so far corroborated by association data. CD109 is a TGF-beta co-receptor and negative regulator, placing it on the same pathway as TGFB1.)
Gene: CD109 hgnc:21685 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CD109 (hgnc:21685). hgnc:21685 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"One locus (denoted by the lead variant rs4464751 in an intron of CD109) is a previously identified linkage locus (OTSC7, 6q13–16.1)"
Establishes both the association and its coincidence with the OTSC7 interval.
SERPINF1 (Contested. Whole-exome sequencing of familial cases reported six rare heterozygous SERPINF1 variants and reduced expression of the stapes-predominant SERPINF1-012 transcript, naming it the first otosclerosis gene. A subsequent resequencing study of 1,604 patients, 1,538 controls and 62 families found no enrichment, and specifically found the reported pathogenic p.Ala131Asp allele in more controls than patients. The evidence items below are deliberately kept as a SUPPORT/REFUTE pair rather than resolved.)
Gene: SERPINF1 hgnc:8824 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SERPINF1 (hgnc:8824). hgnc:8824 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (3 references)
PMID:27056980 SUPPORT Human Clinical
"Six rare heterozygous SERPINF1 variants were found in seven patients in our familial otosclerosis cohort; three are missense mutations predicted to be deleterious to protein function."
The original discovery finding that made SERPINF1 a candidate causal gene.
PMID:30968248 REFUTE Human Clinical
"Our study showed no enrichment of rare variants, stratified by type, in SERPINF1 in patients versus controls."
A much larger resequencing study found no case-control enrichment, contradicting the discovery claim.
PMID:30968248 REFUTE Human Clinical
"the c.392C > A (p.Ala131Asp) variant, previously reported as pathogenic, was identified in three patients and four controls, not replicating its pathogenic nature"
Directly refutes the pathogenicity of the specific allele reported by the discovery study.
COL1A1 (Type I collagen was the first candidate gene proposed, on the strength of its role in bone metabolism and its links to osteogenesis imperfecta and osteoporosis. Targeted replication in a British cohort found no association.)
Gene: COL1A1 hgnc:2197 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COL1A1 (hgnc:2197). hgnc:2197 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED variant_origin: GERMLINE
Show evidence (1 reference)
PMID:29728750 REFUTE Human Clinical
"No evidence of an association was detected with variants in COL1A1, FGF2, BMP2, and PPP2R5B."
A powered replication attempt that failed to confirm the COL1A1 association.
TNFRSF11B (Candidate by function rather than by association: TNFRSF11B encodes osteoprotegerin, whose transcript is reduced in otosclerotic stapes, and homozygous TNFRSF11B variants cause juvenile Paget disease, which can itself cause hearing loss. No variant association with otosclerosis has been established.)
Gene: TNFRSF11B hgnc:11909 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNFRSF11B (hgnc:11909). hgnc:11909 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: UNKNOWN
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"homozygous mutations in TNFRSF11B play a role in Paget’s disease, which may also lead to hearing loss"
Supports candidate status only. The quoted sentence establishes a functional rationale by analogy with juvenile Paget disease, not an otosclerosis variant association, which is why relationship_type is UNKNOWN rather than SUSCEPTIBILITY.
💊

Medical Actions

5
Stapedotomy
Category: Therapeutic Action: stapedotomy with stapes prosthesis placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is stapedotomy with stapes prosthesis placement, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device stapes prosthesis. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
The definitive treatment for fenestral otosclerosis with preserved cochlear reserve. A fenestra is made in the fixed footplate and a prosthesis is placed between the incus and the vestibule, bypassing the ankylosed stapes. Failure rate is around 6% and sensorineural loss is uncommon. Contraindications include an only-hearing ear, active Meniere disease, a persistent stapedial artery and tympanic membrane perforation.
Mechanism Target:
BYPASSES Stapes Footplate Fixation — The prosthesis restores sound transmission across a footplate that remains fixed; the otosclerotic focus itself is untouched, which is why surgery does not arrest the disease.
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"stapedotomy surgery which replaces the fixed stapes bone with a mobile prosthesis"
States that the operation substitutes for the fixed stapes rather than treating the bone lesion.
Target Phenotypes: Progressive conductive hearing impairment HP:0008607 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Progressive conductive hearing impairment (HP:0008607). HP:0008607 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37647735 SUPPORT Human Clinical
"Stapedotomy is currently the most accepted surgical treatment for fenestral otosclerosis with good cochlear reserve."
Establishes stapedotomy as the guideline-endorsed first-line surgical option.
PMID:37647735 SUPPORT Human Clinical
"Stapedotomy is usually a safe procedure, with good results, few complications, and a failure rate of approximately 6%."
Supports the safety and failure-rate statement in the description.
Hearing aid amplification
Category: Therapeutic Action: hearing aid amplificationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hearing aid amplification, annotated with Rehabilitation (NCIT:C15315), qualified as medical device hearing aid. NCIT:C15315 is a clinical intervention from the NCI Thesaurus. Ontology label: Rehabilitation NCIT:C15315
Platform: Device
A well-indicated non-surgical alternative for patients who decline or are unfit for stapes surgery, and the recommended option after stapedotomy in severe mixed loss with a large residual air-bone gap. The guideline notes a worse cost-benefit ratio than surgery.
Target Phenotypes: Progressive conductive hearing impairment HP:0008607 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Progressive conductive hearing impairment (HP:0008607). HP:0008607 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"The use of hearing aids is well indicated for the treatment of patients with otosclerosis. However, when compared with stapes surgery, the cost-benefit ratio is worse"
Task-force recommendation stating both the indication and its cost-benefit caveat.
Cochlear implantation
Category: Therapeutic Action: cochlear device implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cochlear device implantation, annotated with Surgical Procedure (NCIT:C15329), qualified as medical device cochlear implant. NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Device
Reserved for advanced cochlear otosclerosis with profound deafness, on the same indications as any other cause of profound loss. Round-window and basal-turn ossification is a specific hazard, so MRI is required before implantation, and perimodiolar electrodes reduce facial nerve stimulation.
Target Phenotypes: Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:37647735 SUPPORT Human Clinical
"Patients with advanced otosclerosis are at increased risk of ossification of the round window membrane and basal turn, and the surgeon should order MRI as a mandatory test to prevent complications during the insertion of electrode array"
Supports both the indication in advanced disease and the ossification hazard described here.
PMID:28874211 SUPPORT Human Clinical
"Stapes surgery is a suitable treatment option for patients with advanced otosclerosis, and should be considered mandatory, before offering cochlear implantation, for those with a demonstrable conductive component to their hearing loss."
Constrains when cochlear implantation is the right operation: in advanced disease with a residual air-bone gap, stapes surgery comes first, and implantation is for the minority who gain little from it.
PMID:39155792 SUPPORT Human Clinical
"Word recognition scores before surgery averaged 7.4% (at 70 dB) and increased significantly to 66.2% about 12 months after surgery."
Quantifies the benefit this treatment is offered for, which the other two items constrain but do not measure. The cohort is 17 patients with far-advanced otosclerosis who had already had stapes surgery, so the figure describes implantation as the second operation rather than the first.
Sodium fluoride
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sodium fluoride CHEBI:28741 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium fluoride (CHEBI:28741). CHEBI:28741 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Used for decades on the rationale that fluoride inactivates proteolytic enzymes driving otic-capsule bone turnover. The 2023 task force grades the evidence as insufficient: no adequately designed study supports the indication.
Mechanism Target:
INHIBITS Focal Otospongiotic Bone Resorption — Intended to suppress the resorptive phase; the mechanism is a rationale rather than a demonstrated effect in otosclerotic bone.
Show evidence (1 reference)
PMID:37647735 SUPPORT INDIRECT Human Clinical
"Fluoride ingestion may influence the prevalence of diseases with abnormal bone resorption."
States the proposed target of the therapy. It is a general statement about bone resorption rather than a measured effect on otosclerotic foci, hence INDIRECT.
Show evidence (1 reference)
PMID:37647735 REFUTE Human Clinical
"Sodium fluoride has been used for decades to treat patients with otosclerosis. However, well-designed studies are lacking to support its indication (Insufficient evidence)."
The guideline finds the evidence insufficient, which cuts against the treatment's efficacy claim; recorded as REFUTE for that reason, not because harm was shown.
Bisphosphonate therapy
Category: Therapeutic Action: Bisphosphonate TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Bisphosphonate Therapy (NCIT:C198585). NCIT:C198585 is a clinical intervention from the NCI Thesaurus. NCIT:C198585
Platform: Small molecule
Tried as an antiresorptive for otospongiotic disease. Control imaging improves but clinical benefit is at most slight, and the task force grades the evidence as insufficient.
Mechanism Target:
INHIBITS Focal Otospongiotic Bone Resorption — Antiresorptive suppression of the active otospongiotic phase; radiologic change is reported without a matching clinical effect.
Show evidence (1 reference)
PMID:37647735 SUPPORT INDIRECT Human Clinical
"The use of bisphosphonates has shown radiologic improvement on control scans, but only slight clinical improvement in patients."
Radiologic improvement of the focus is a surrogate for suppressed resorption, so it supports the mechanism indirectly while the same sentence limits the clinical claim.
Show evidence (1 reference)
PMID:37647735 REFUTE Human Clinical
"Higher-quality studies are still lacking to support their indication in patients with otosclerosis (Insufficient evidence)."
The guideline declines to endorse bisphosphonates, cutting against a clinical efficacy claim.
🌍

Environmental Factors

3
Persistent measles virus infection of the otic capsule
No `exposure_term:` is bound. ECTO was searched (`runoak -i sqlite:obo:ecto`) for measles, virus and viral-exposure terms and returned nothing suitable; the ECTO virus-exposure branch does not carry a measles term, and no term beats a wrong term.
The longest-standing environmental hypothesis. Measles virus RNA has been recovered from otosclerotic stapes footplates in many series and the incidence of otosclerosis fell steeply in the decades after mass measles vaccination. Other series using comparable RT-PCR methods have detected nothing at all. The hypothesis is therefore recorded here with both a supporting and a refuting primary study rather than as a settled cause.
Show evidence (2 references)
PMID:32968571 SUPPORT Other
"The majority of the current literature supported the presence of the measles virus component in the otosclerotic stapes samples and its role in the etiopathogenesis of otosclerosis."
A systematic review of 52 relevant articles reporting that most, though not all, support the association; graded OTHER because it is a synthesis, not primary data.
PMID:32968571 REFUTE Other
"On the contrary, five observational studies reported no evidence of the association."
The same review counts the studies that found nothing; recorded as a separate REFUTE item because one evidence item cannot carry two opposite claims.
Mechanism Target:
TRIGGERS Local Proinflammatory Cytokine Expression in the Otosclerotic Focus — Proposed route: persistent viral antigen in the focus drives local proinflammatory cytokine expression and osteoclast activation in a bone that is otherwise not remodeled.
Show evidence (3 references)
PMID:24676726 SUPPORT INDIRECT Human Clinical
"The presence of measles virus RNA was noted in 80.3 % of otosclerotic stapes (49 out of 61) and 9.7 % of normal tissues (3 out of 31)."
A case-control detection difference in surgically removed stapes versus cadaveric controls. It shows association with the diseased tissue, not that the virus initiates remodeling, hence INDIRECT.
PMID:24676726 SUPPORT INDIRECT Human Clinical
"The presence of TNF-α and IL-1β mRNA in the virus-positive stapes could be the result of viral antigen stimulation and may be a marker of inflammation the otosclerotic focus."
States the proposed antigen-to-cytokine step of this link; the source's own hedging ("could be", "may be") is why it is graded INDIRECT.
PMID:28971731 REFUTE Human Clinical
"No sample was positive for any of 3 measles virus genes (H, N, and F). Measles virus RNA was not detected in any sample by real-time RT-PCR."
A 93-patient cross-sectional study using real-time RT-PCR for three measles genes that found no virus at all, directly contradicting the detection studies.
Fluoride in drinking water
exposure to fluoride in drinking water ECTO:9000423 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to fluoride in drinking water, annotated with exposure to fluoride (ECTO:9000423). ECTO:9000423 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Clinical otosclerosis has been reported to be commoner in low-fluoride areas, and sodium fluoride is proposed to neutralise proteolytic enzymes implicated in abnormal otic-capsule bone metabolism. This is the rationale behind fluoride supplementation as a medical therapy, which has never been supported by adequately designed trials.
Show evidence (1 reference)
PMID:37647735 SUPPORT INDIRECT Human Clinical
"An epidemiological study on otosclerosis and fluoridated drinking water showed a higher prevalence of clinical otosclerosis in low-fluoride areas."
An ecological prevalence comparison, reported second-hand by the task force; it supports an inverse association, not a demonstrated protective effect, hence INDIRECT.
Mechanism Target:
PROTECTS_AGAINST Focal Otospongiotic Bone Resorption — Proposed mechanism for the inverse association: fluoride inactivates proteolytic enzymes that drive abnormal bone metabolism in the otic capsule.
Show evidence (1 reference)
PMID:37647735 SUPPORT INDIRECT Human Clinical
"Sodium fluoride neutralizes proteolytic enzymes that can cause abnormal bone metabolism, such as the Diastrophic Dysplasia Sulfate Transporter"
States the proposed biochemical mechanism behind the protective claim; it is a mechanistic rationale rather than a measurement in otosclerotic bone, hence INDIRECT.
Pregnancy and endogenous estrogen exposure
No `exposure_term:` bound: this entry records the absence of an effect, and binding an ECTO exposure term would imply an asserted exposure-disease relationship the evidence refutes.
A long-held clinical belief, resting on the roughly 2:1 female predominance and on reports of hearing deterioration around pregnancy. A population-based case-control study of 299 cases and 897 matched controls found no association with parity or with prior bilateral oophorectomy. It is recorded here as a refuted risk factor, with no mechanism link asserted.
Show evidence (2 references)
PMID:33107781 REFUTE Human Clinical
"These data do not support a relationship between endogenous estrogen exposure and development of otosclerosis."
The study's own conclusion, from 1196 women, refutes the proposed estrogen risk factor.
PMID:33107781 REFUTE Human Clinical
"The odds ratio for the association of ≥1 delivery with otosclerosis was 1.16 (95% confidence interval [CI] 0.85-1.60; P = .35)."
The null point estimate and confidence interval behind that conclusion.
🔬

Diagnosis

2
Pure-tone audiometry with Carhart notch and absent acoustic reflexes
The diagnostic core: a conductive or mixed loss with an air-bone gap, a Carhart notch (an artefactual bone-conduction dip around 2 kHz produced by the fixed ossicular chain), absent stapedial reflexes and a type A or As tympanogram. In a typical case this constellation makes imaging largely unnecessary.
Show evidence (2 references)
PMID:33107781 SUPPORT Human Clinical
"Clinical and audiologic assessments included the presence of a Carhart notch, absent acoustic reflexes, and a type A or As tympanogram."
These are the criteria actually used to ascertain otosclerosis cases in a population-based study, so they document diagnostic practice rather than merely recommending it.
PMID:37647735 SUPPORT Human Clinical
"family history of otosclerosis, and successful stapes surgery in one of the ears gain little benefit from imaging"
Supports the statement that imaging adds little in a typical audiometrically classic case.
High-resolution temporal bone CT
Indicated before stapes surgery and when the presentation is atypical — mixed or sensorineural loss, fluctuating hearing, prior ear surgery or trauma, vestibular complaints, or a child with mixed loss (to exclude X-linked mixed deafness).
high-resolution temporal bone computed tomography NCIT:C17204 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"Mastoid HRCT is the imaging modality of choice for patients with a clinical indication for stapes surgery"
Establishes CT as the preoperative imaging modality of choice.
🩻

Imaging Findings

1
Fissula Ante Fenestram Radiolucency on Temporal Bone CT
A hypodense (radiolucent) focus at the fissula ante fenestram, or pericochlear lucency in more extensive disease. High-resolution CT of the mastoid is the imaging modality of choice when stapes surgery is planned.
Ct Focal
bony otic capsule UBERON:0005411 Uberon multi-species anatomy ontology (UBERON)
Show evidence (2 references)
PMID:33107781 SUPPORT Human Clinical
"Imaging criteria included radiolucency in the otic capsule at the fissula ante fenestram or surrounding the otic capsule."
States the imaging criterion, here used as a diagnostic criterion in a population-based case ascertainment.
PMID:37647735 SUPPORT Human Clinical
"Mastoid HRCT is the imaging modality of choice for patients with a clinical indication for stapes surgery"
Supports the modality assignment.
📈

Progression

2
Onset
Age: Second to fifth decade, most often the third
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"Symptomatic otosclerosis most frequently occurs in working-age individuals between the second and fifth decades"
Gives the age band recorded for this phase.
Progression to bilateral disease
Onset is usually unilateral; most patients eventually have both ears involved.
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"Initial manifestation is often limited to one ear, but eventual bilateral disease is observed in 70–80% of cases"
Gives the unilateral-to-bilateral course recorded for this phase.
🪜

Stages

3
Histologic otosclerosis
An otic-capsule focus that has not reached a site where it fixes the stapes or the round window, and so causes no symptoms. It is found only by sectioning temporal bones at autopsy, in roughly an order of magnitude more people than have clinical disease. Only some 12-15% of temporal bones with histologic otosclerosis show stapedial fixation.
Show evidence (2 references)
PMID:11568664 SUPPORT Human Clinical
"Histologic otosclerosis is a disease process without clinical symptoms or manifestations that can be discovered only by sectioning of the temporal bone at autopsy."
Defines this stage and how it is ascertained.
PMID:11568664 SUPPORT Human Clinical
"Some 12% to 15% of temporal bones with histologic otosclerosis have demonstrated stapedial fixation."
Quantifies the fraction of histologic foci that progress to the clinical stage.
Clinical otosclerosis
A focus sited so that it interferes with stapes motion or the round window membrane, producing conductive hearing loss with tinnitus and sometimes vestibular symptoms. This is the stage at which patients present.
Show evidence (1 reference)
PMID:11568664 SUPPORT Human Clinical
"Clinical otosclerosis is otosclerosis at a site where it causes conductive hearing loss by interfering with the motion of the stapes or of the round window membrane."
Defines this stage by lesion site rather than by lesion size.
Cochlear (far-advanced) otosclerosis
Extensive otic-capsule involvement reaching the cochlear endosteum. Sensorineural loss is added or predominates, thresholds may reach implant-eligible levels, and round-window or basal-turn ossification can complicate cochlear implantation.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"Cochlear otosclerosis refers to invasion of the cochlear endosteum with extensive involvement of the otic capsule, without stapes fixation, leading to NSHL, tinnitus, and vestibular symptoms."
Defines this stage as the task force does.
📊

Prevalence

3
Populations of European descent
Point Prevalence 340.0 per 100,000 (300.0–380.0) >1 in 1,000
Clinical (symptomatic) otosclerosis, 0.30-0.38%.
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"Clinical otosclerosis has an estimated prevalence of 0.30–0.38% in populations of European descent"
Gives the population, measure and rate recorded here.
Temporal bone autopsy specimens
Point Prevalence 2500.0 per 100,000 >1 in 1,000
Histologic otosclerosis — otic-capsule bony overgrowth without clinical symptoms. Roughly an order of magnitude commoner than clinical disease, because only a minority of foci reach a site that fixes the stapes.
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"Histologic otosclerosis without clinical symptoms is more frequent, with bony overgrowth observed in as many as 2.5% of temporal bone autopsy specimens"
Gives the autopsy-series rate recorded here.
Olmsted County, Minnesota, USA, 2015-2017
Annual Incidence 3.2 per 100,000 1–9 per 100,000 per year
Rochester Epidemiology Project, 614 incident cases 1950-2017. The nadir of a steep decline from a 1970-74 peak of 18.5 per 100,000 person-years.
Show evidence (1 reference)
PMID:32925838 SUPPORT Human Clinical
"The incidence rose from 8.9 per 100,000 person-years in the 1950s to a peak of 18.5 from 1970 to 1974. From this peak, the incidence significantly declined to 6.2 per 100,000 person-years by the early-1990s and reached a nadir of 3.2 from 2015 to 2017"
Gives the modern incidence and the trajectory behind it.
⚖️

Clinical Burden

Moderate
Untreated otosclerosis causes progressive, usually bilateral hearing loss that begins in working life, but it is not life-limiting and the conductive component is correctable by stapes surgery or amplification in the great majority of patients.
Show evidence (1 reference)
PMID:36653343 SUPPORT Human Clinical
"Symptomatic otosclerosis most frequently occurs in working-age individuals between the second and fifth decades"
Establishes onset in working life, which is what makes the hearing loss burdensome.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Otosclerosis:

Superior semicircular canal dehiscence
Overlapping Features A third-window lesion that produces an air-bone gap with an intact tympanic membrane and can be mistaken for otosclerosis. It is also an explicit contraindication to stapedotomy, so distinguishing it changes management.
Distinguishing Features
  • Supranormal bone conduction thresholds and abnormal VEMP responses despite the air-bone gap.
  • Sound- and pressure-evoked vestibular symptoms, with dehiscence visible on CT.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"Ménière’s disease or superior semicircular canal dehiscence are contraindications to stapedotomy (Insufficient evidence)."
Establishes why this differential must be resolved before surgery.
Meniere disease
Overlapping Features Overlaps otosclerosis in vestibular symptoms and fluctuating hearing, and is a relative contraindication to stapedotomy. Endolymphatic hydrops is itself seen in some patients with otosclerosis involving the spiral ligament, which blurs the boundary.
Distinguishing Features
  • Episodic vertigo with fluctuating low-frequency sensorineural loss and aural fullness, rather than a stable air-bone gap.
Show evidence (1 reference)
PMID:37647735 SUPPORT Human Clinical
"Vestibular complaints should be investigated during clinical evaluation, as misdiagnosis can have significant implications on treatment outcomes, especially in patients with Ménière’s disease, an enlarged vestibular aqueduct, or superior semicircular canal dehiscence."
Names the differentials that matter and says why getting them wrong changes outcomes.
🐁

Animal Models

1
Smarca4 E1548K knock-in mouse
The only animal model of otosclerosis. Mice carrying the mouse orthologue of the human kindred's SMARCA4 variant are hearing-impaired on acoustic startle and auditory brainstem response testing, and micro-CT shows a highly irregular incus disrupting the ossicular chain.
Species
Mouse
Genotype
Smarca4+/E1548K (CRISPR-Cas9 knock-in of the orthologue of the human SMARCA4 p.E1548K variant)
Publication
PMID:37399313
Show evidence (1 reference)
PMID:37399313 SUPPORT Model Organism
"We generated CRISPR-Cas9 transgenic mice carrying the human mutation in the mouse SMARCA4 orthologue."
Documents how the model was made and that it carries the orthologue of the human kindred's allele.
{ }

Source YAML

click to show 
name: Otosclerosis
creation_date: '2026-09-09T00:00:00Z'
category: Complex
description: >-
  Otosclerosis is a bone dystrophy confined to the otic capsule — the endochondral
  bone shell of the inner ear, which in health is one of the least remodeled bones
  in the body. In otosclerosis that quiescence is lost focally: osteoclasts resorb
  endochondral bone at discrete foci, most often at the fissula ante fenestram just
  anterior to the oval window, and osteoblasts then replace the resorbed bone with
  disorganized, poorly organized new bone. The active, hypervascular resorptive
  phase is called otospongiosis; the inactive, densely mineralized end state is
  otosclerosis proper, and both appear in the same temporal bone.

  The lesion causes disease by where it sits rather than by how much bone it
  destroys. A focus that reaches the annular ligament ankyloses the stapes
  footplate in the oval window, and sound can no longer be transmitted through the
  ossicular chain — progressive conductive hearing loss, typically beginning in the
  third decade and bilateral in most patients. Medial extension to the cochlear
  endosteum adds a sensorineural component, giving mixed hearing loss.

  Two features frame the etiology. Around half of patients have an affected
  relative, and the familial pattern is autosomal dominant with reduced penetrance,
  but two decades of linkage mapping produced ten OTSC intervals and almost no
  genes; a 2023 three-biobank GWAS instead found 27 common risk loci and confirmed
  a polygenic architecture, with the nearest genes clustering on bone remodeling,
  mineralization and TGF-beta signalling. And the disease is disappearing: US
  population incidence fell from 18.5 per 100,000 person-years in the early 1970s
  to 3.2 by 2015-2017, a decline widely — but not conclusively — attributed to
  measles vaccination, since measles virus RNA has been recovered from otosclerotic
  stapes in some series and not at all in others.
disease_term:
  preferred_term: otosclerosis
  term:
    id: MONDO:0005349
    label: otosclerosis
synonyms:
- otospongiosis
- stapedial otosclerosis
- cochlear otosclerosis
- clinical otosclerosis
parents:
- Disorder of the Middle Ear
- Metabolic Bone Disease
classifications:
  harrisons_chapter:
  - classification_value: DISORDER_OF_EAR
    evidence:
    - reference: PMID:36653343
      reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Otosclerosis is an exclusively human disorder characterized by pathologic remodeling of the bone encasing the inner ear, called the otic capsule
      explanation: Places the disease squarely in the ear, as a disorder of the bone encasing the inner ear.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Assigned for the heritable-susceptibility axis: roughly half of patients have
      an affected relative, familial disease segregates as autosomal dominant with
      reduced penetrance, and non-familial disease is polygenic with environmental
      contributions.
    evidence:
    - reference: PMID:36653343
      reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Otosclerosis is highly familial, with a positive family history reported for 50–60% of cases
      explanation: Supports treating heritable susceptibility as a defining axis of the disease.
clinical_burden:
  burden_level: MODERATE
  rationale: >-
    Untreated otosclerosis causes progressive, usually bilateral hearing loss that
    begins in working life, but it is not life-limiting and the conductive component
    is correctable by stapes surgery or amplification in the great majority of
    patients.
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Symptomatic otosclerosis most frequently occurs in working-age individuals between the second and fifth decades
    explanation: Establishes onset in working life, which is what makes the hearing loss burdensome.
pathophysiology:
- name: Reduced Osteoprotegerin Restraint of Osteoclastogenesis
  description: >-
    In health the otic capsule is protected from remodeling by osteoprotegerin,
    secreted in large amounts by the spiral ligament, which acts as a decoy receptor
    for RANKL and suppresses osteoclast recruitment and activation. Osteoprotegerin
    transcript is significantly reduced in otosclerotic stapes footplates relative to
    normal stapes, releasing that restraint.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: negative regulation of osteoclast differentiation
    term:
      id: GO:0045671
      label: negative regulation of osteoclast differentiation
    modifier: DECREASED
  genes:
  - preferred_term: TNFRSF11B
    description: Encodes osteoprotegerin (OPG).
    term:
      id: hgnc:11909
      label: TNFRSF11B
  locations:
  - preferred_term: bony otic capsule
    term:
      id: UBERON:0005411
      label: bony otic capsule
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This is explained by the presence of OPG, a mediator produced in large quantities by the spiral ligament that inhibits the recruitment, formation, and activation of osteoclasts.
    explanation: States the osteoprotegerin mechanism that normally holds otic-capsule remodeling in check.
  - reference: PMID:24676726
    reference_title: "Expression of TNF-α, OPG, IL-1β and the presence of the measles virus RNA in the stapes of the patients with otosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The OPG expression level was significantly lower in otosclerotic tissues comparing to controls.
    explanation: Measures the loss of that restraint directly in otosclerotic stapes versus cadaveric control stapes.
  downstream:
  - target: Loss of Otic Capsule Remodeling Quiescence
    causal_link_type: DIRECT
    description: >-
      Withdrawal of osteoprotegerin's decoy-receptor restraint permits RANKL-driven
      osteoclast recruitment in a bone that is otherwise not remodeled.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Therefore, low levels of OPG may be related to pathological new bone formation and resorption.
      explanation: The cited task force draws exactly this causal step from low osteoprotegerin to pathological remodeling.
  notes: >-
    Deliberately not declared conformant to
    osteoporosis_bone_resorption#RANKL-Driven Osteoclastogenesis. That module scopes
    itself to the osteoporoses and its chain terminates in net bone loss and skeletal
    fragility; otosclerosis is focal, confined to one bone that is normally not
    remodeled at all, and ends in net sclerosis rather than fragility. The
    RANKL/osteoprotegerin step is a parallel use of the same axis, not a conforming
    instance of that module's chain.
- name: Local Proinflammatory Cytokine Expression in the Otosclerotic Focus
  description: >-
    Otosclerotic footplates express TNF-alpha and IL-1beta transcripts at levels
    significantly above normal stapes, marking the focus as an inflammatory lesion
    and supplying two of the classical osteoclast-activating cytokines.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:24676726
    reference_title: "Expression of TNF-α, OPG, IL-1β and the presence of the measles virus RNA in the stapes of the patients with otosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The transcript level of TNF-α and IL-1β was significantly higher in otosclerotic tissues comparing to normal tissue.
    explanation: Directly measures the elevated cytokine transcripts in surgically removed otosclerotic stapes.
  downstream:
  - target: Focal Otospongiotic Bone Resorption
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      TNF-alpha and IL-1beta are osteoclast-activating cytokines; their presence in
      the focus alongside absent osteoprotegerin is read by the source as the
      signature of active bone remodeling in the stapes.
    evidence:
    - reference: PMID:24676726
      reference_title: "Expression of TNF-α, OPG, IL-1β and the presence of the measles virus RNA in the stapes of the patients with otosclerosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The lack of OPG mRNA and the presence of TNF-α and IL-1β mRNA in the majority of otosclerotic tissues reflect the bone remodeling process occurring in the stapes.
      explanation: The authors themselves link the cytokine profile to the remodeling process in the focus.
- name: Dysregulated TGF-beta Signaling in the Otic Capsule
  description: >-
    TGF-beta1 regulates both osteoblast and osteoclast lineages and is produced
    within the otic capsule and by inner-ear tissues from which it can diffuse. An
    intronic TGFB1 variant is genome-wide significant for otosclerosis, and several
    further risk loci (SMAD3, CD109, LTBP3, AHSG, and a haplotype overlapping RUNX2)
    lie on the same pathway, making TGF-beta signalling the most consistently
    implicated molecular axis.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: DYSREGULATED
  genes:
  - preferred_term: TGFB1
    term:
      id: hgnc:11766
      label: TGFB1
  - preferred_term: SMAD3
    term:
      id: hgnc:6769
      label: SMAD3
  - preferred_term: CD109
    term:
      id: hgnc:21685
      label: CD109
  - preferred_term: LTBP3
    term:
      id: hgnc:6716
      label: LTBP3
  - preferred_term: AHSG
    term:
      id: hgnc:349
      label: AHSG
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.
    explanation: The GWAS meta-analysis itself identifies TGF-beta signalling as the recurring pathway across its risk loci.
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other genes relevant for TGFβ signalling include SMAD3, CD109, LTBP3, and AHSG, all of which are nearest to the lead variants in their respective loci, and RUNX2 which partly overlaps an association signal"
    explanation: Names the specific pathway members behind this node's gene list.
  downstream:
  - target: Loss of Otic Capsule Remodeling Quiescence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      TGF-beta1 is proposed to reach the otic capsule paracrine from inner-ear tissue
      and regulate its remodeling; the step from altered signalling to loss of
      quiescence is inferred from the genetics rather than demonstrated in human
      otic capsule.
    evidence:
    - reference: PMID:36653343
      reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "As a secreted molecule, TGFβ1 could diffuse from these cells into the surrounding otic capsule to regulate its remodeling in a paracrine fashion."
      explanation: The authors state the proposed route from TGF-beta1 to otic-capsule remodeling; the wording is hypothetical, hence INDIRECT.
- name: Loss of Otic Capsule Remodeling Quiescence
  description: >-
    The mature otic capsule is a near-static bone: osteoblast and osteoclast activity
    is almost absent, and turnover runs at roughly 0.13% per year against about 10%
    in ordinary skeletal bone. In otosclerosis both lineages are reactivated at focal
    sites, most plausibly at the residual islands of immature cartilage (globuli
    interossei) retained in the human capsule.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: bone remodeling
    term:
      id: GO:0046849
      label: bone remodeling
    modifier: INCREASED
  locations:
  - preferred_term: bony otic capsule
    term:
      id: UBERON:0005411
      label: bony otic capsule
  evidence:
  - reference: PMID:37399313
    reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: under normal conditions, osteoblast and osteoclast activity of bone turnover is almost entirely absent in the mature otic capsule
    explanation: Establishes the baseline quiescence whose loss defines this node.
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The otic capsule contains regions of immature cartilage called globuli interossei, which may correspond to the earliest loci of otosclerosis.
    explanation: Identifies the candidate cellular substrate where quiescence is first lost.
  downstream:
  - target: Focal Otospongiotic Bone Resorption
    causal_link_type: DIRECT
    description: >-
      Reactivation of osteoclasts within the capsule is the first half of the
      remodeling cycle that produces the otosclerotic focus.
    evidence:
    - reference: PMID:37399313
      reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In otosclerosis, through a poorly understood mechanism, osteoblasts and osteoclasts are activated and initiate abnormal bone remodeling: endochondral bone in the otic capsule is reabsorbed by osteoclasts, followed by deposition of new dense mineralized bone by osteoblasts, ultimately resulting in otosclerotic foci"
      explanation: States the causal order — activation of both lineages, then resorption — that this edge asserts.
- name: Focal Otospongiotic Bone Resorption
  description: >-
    The active phase. Bone is resorbed around vessels and replaced by fibrous
    connective tissue, the perivascular spaces enlarge into vascular channels, and
    the focus becomes hypervascular and hypercellular with osteoclastic giant cells.
    The commonest site is the fissula ante fenestram immediately anterior to the oval
    window. While active the lesion is termed otospongiosis.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: multinuclear osteoclast
    term:
      id: CL:0000779
      label: multinuclear osteoclast
  biological_processes:
  - preferred_term: bone resorption
    term:
      id: GO:0045453
      label: bone resorption
    modifier: INCREASED
  locations:
  - preferred_term: bony otic capsule
    term:
      id: UBERON:0005411
      label: bony otic capsule
    spatial_extent: FOCAL
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Otosclerosis only affects the temporal bone, particularly the fissula ante fenestram, but may extend to the region of the labyrinth and cochlea, oval window, and round window.
    explanation: Establishes the focal site of onset and the routes of extension.
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bone is resorbed around a vessel and replaced by a fibrous connective tissue. These areas of active disease are characterized by the presence of osteoclastic giant cells and vascular proliferation.
    explanation: Describes the resorptive, hypervascular tissue architecture of the active focus.
  downstream:
  - target: Sclerotic Bone Replacement of the Focus
    causal_link_type: DIRECT
    description: >-
      Within the resorbed space reticular cells and fibroblasts take on osteoblast
      form, matrix calcification begins, and immature bone is laid down — the
      resorptive phase converting into the sclerotic one.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Within this space, reticular cells and fibroblasts assume the form of osteoblasts. At the same time, calcification begins in the matrix and a new, immature bone is formed with a bluish stain on H&E.
      explanation: States the transition from the resorbed space to new bone formation, which is what this edge asserts.
  - target: Schwartze Sign
    causal_link_type: DIRECT
    description: >-
      Anastomoses between the hypervascular active focus and submucosal vessels of
      the cochlear promontory produce the promontory hyperemia visible through the
      tympanic membrane.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hyperemia may sometimes be observed on the cochlear promontory and is characterized by anastomoses between the otosclerotic foci (with superficial venous lakes) and vessels of the cochlear promontory submucosa, which can be seen through the tympanic membrane.
      explanation: Names the vascular connection from the active focus to the visible promontory sign.
- name: Sclerotic Bone Replacement of the Focus
  description: >-
    Osteoblasts replace the resorbed bone with dense, disorganized, poorly organized
    new bone that does not respect the normal contours of the labyrinth or ossicles
    and may become exophytic into the middle ear and perilymphatic space. In this
    inactive state the lesion is termed otosclerosis proper.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: INCREASED
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: INCREASED
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Depending on whether the disease is active or inactive, it is termed otospongiosis (active) or otosclerosis (inactive).
    explanation: Establishes the two-phase naming this node and its upstream node represent.
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The otosclerotic process does not respect the normal limits and contours of the labyrinth or ossicles and may become exophytic and extend into the middle ear and perilymphatic space.
    explanation: Describes the disorganized expansion of the sclerotic focus beyond normal bone boundaries.
  downstream:
  - target: Stapes Footplate Fixation
    causal_link_type: DIRECT
    description: >-
      Expansion of the focus at the anterior oval window ankyloses the adjacent
      stapes footplate.
    evidence:
    - reference: PMID:37399313
      reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: which upon expansion causes fixation of the adjacent stapedial footplate, impairing free motion of the stapes bone and culminating in progressive conductive hearing loss
      explanation: States expansion of the focus as the direct cause of footplate fixation.
  - target: Cochlear Endosteal Involvement
    causal_link_type: DIRECT
    description: >-
      Medial rather than lateral progression of the same focus carries the lesion to
      the cochlear endosteum.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Lesions that originate in the fissula ante fenestram and involve the annular ligament cause conductive deafness, whereas medial progression to the cochlear endosteum causes sensorineural deafness.
      explanation: Contrasts the two directions of spread from the same focus, which is what this edge and its sibling represent.
- name: Stapes Footplate Fixation
  description: >-
    Otosclerotic bone bridging the stapediovestibular joint ankyloses the footplate
    within the oval window. The ossicular chain can no longer transfer tympanic
    vibration to the perilymph, and an air-bone gap appears on audiometry.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  locations:
  - preferred_term: stapes base
    term:
      id: UBERON:0002496
      label: stapes base
  - preferred_term: oval window
    term:
      id: UBERON:0002501
      label: oval window
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In classic otosclerosis, the conduction of sound through the ossicular chain is impeded due to fixation of the stapes footplate by pathologic bone remodeling, leading to conductive hearing loss."
    explanation: States the mechanical consequence of footplate fixation that defines this node.
  downstream:
  - target: Progressive Conductive Hearing Loss
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37399313
      reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: impairing free motion of the stapes bone and culminating in progressive conductive hearing loss
      explanation: Carries the causal step from fixed footplate to the audiometric phenotype.
- name: Cochlear Endosteal Involvement
  description: >-
    Medial extension of the focus into the cochlear endosteum damages intracochlear
    structures and adds a sensorineural component. Reported rates differ by series
    and by whether the criterion is histologic involvement or measured sensorineural
    loss: up to 10% of cases by one account, 20-30% by another. Involvement of the
    spiral ligament and of the saccular neuroepithelium is the proposed basis for the
    vestibular symptoms that accompany endosteal disease.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  locations:
  - preferred_term: cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When bone remodeling progresses to involve the cochlear endosteum, otosclerosis can cause additional sensorineural hearing loss in 20–30% of patients, which reflects damage to the delicate intracochlear cells."
    explanation: States both the anatomical step and the sensorineural consequence.
  - reference: PMID:37399313
    reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in up to 10% of cases otosclerotic foci involve the cochlear endosteum that may also manifest as sensorineural or mixed hearing loss
    explanation: >-
      Cited alongside the 20-30% figure because the two sources disagree; recorded so the
      disagreement is visible rather than resolved by picking one number.
  downstream:
  - target: Sensorineural Hearing Loss
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: whereas medial progression to the cochlear endosteum causes sensorineural deafness
      explanation: States endosteal involvement as the cause of the sensorineural component.
  - target: Mixed Hearing Loss
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: whereas medial progression to the cochlear endosteum causes sensorineural deafness
      explanation: >-
        Supports the sensorineural component that, added to the persisting conductive
        component, constitutes the mixed loss.
  - target: Vestibular Symptoms
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Saccular type I hair-cell loss is seen only when endosteal involvement is
      present; the intervening step (toxic metabolites released into inner-ear fluids,
      or endolymphatic hydrops) is not settled.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: found a reduction in the mean density of type I HCs in the saccule of patients with otosclerosis, but only when endosteal involvement was present.
      explanation: >-
        Ties vestibular end-organ damage specifically to endosteal involvement; the
        mechanism connecting them is stated as a hypothesis in the same source, so INDIRECT.
phenotypes:
- name: Progressive Conductive Hearing Loss
  category: Auditory
  description: >-
    The defining manifestation of clinical otosclerosis: a slowly progressive
    conductive loss with an air-bone gap, usually beginning in the second to fourth
    decade and eventually bilateral in most patients.
  diagnostic: true
  phenotype_term:
    preferred_term: Progressive conductive hearing impairment
    term:
      id: HP:0008607
      label: Progressive conductive hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The classic presentation of otosclerosis consists of progressive conductive hearing loss in adulthood.
    explanation: States the phenotype and its course directly.
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Initial manifestation is often limited to one ear, but eventual bilateral disease is observed in 70–80% of cases
    explanation: Supports the laterality course described for this phenotype.
  sequelae:
  - target: Paracusis of Willis
    causal_link_type: DIRECT
    description: >-
      The conductive loss attenuates background noise more than speech, so
      intelligibility can improve in a noisy setting.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This phenomenon is known as Paracusis of Willis, in which the conductive hearing loss subdues the background noise such that it improves the signal-to-noise ratio for the patient."
      explanation: States that the conductive loss itself produces the paracusis, which is what this edge asserts.
- name: Mixed Hearing Loss
  category: Auditory
  description: >-
    Where the focus reaches the cochlear endosteum a sensorineural component is added
    to the persisting conductive one.
  phenotype_term:
    preferred_term: Mixed hearing impairment
    term:
      id: HP:0000410
      label: Mixed hearing impairment
  evidence:
  - reference: PMID:37399313
    reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in up to 10% of cases otosclerotic foci involve the cochlear endosteum that may also manifest as sensorineural or mixed hearing loss
    explanation: Names mixed hearing loss as a manifestation of endosteal involvement.
- name: Sensorineural Hearing Loss
  category: Auditory
  description: >-
    Cochlear otosclerosis — extensive otic-capsule involvement without stapes
    fixation — presents as sensorineural loss. A profound deficit across all
    frequencies is rare but is the indication for cochlear implantation.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:34633540
    reference_title: A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients typically present with conductive HL which often progresses to mixed loss (cochlear otosclerosis); purely sensorineural hearing loss (SNHL) is rare.
    explanation: Establishes both that pure sensorineural loss occurs and that it is the uncommon presentation.
- name: Tinnitus
  category: Auditory
  description: Ringing or buzzing accompanying the hearing loss.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Tinnitus is a highly prevalent symptom.
    explanation: >-
      Supports both the phenotype and the FREQUENT band; the source gives a qualitative
      "highly prevalent" rather than a percentage, which maps to FREQUENT.
- name: Vestibular Symptoms
  category: Vestibular
  description: >-
    Dizziness, vertigo and imbalance, reported in a substantial minority. They matter
    clinically because they overlap with Meniere disease, enlarged vestibular
    aqueduct and superior semicircular canal dehiscence, all of which change surgical
    management. Reported in up to 40% of patients; `frequency:` is left unset because
    "up to 40%" bounds the estimate rather than giving a band.
  phenotype_term:
    preferred_term: Vestibular symptoms
    term:
      id: HP:0001751
      label: Abnormal vestibular function
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Vestibular symptoms have been reported in up to 40% of patients with otosclerosis.
    explanation: Supports the phenotype and the upper bound quoted in the description.
- name: Paracusis of Willis
  category: Auditory
  description: >-
    Improved speech clarity in noisy surroundings, a classical if inconstant symptom
    of conductive loss. There is no HPO term for it, so the descriptor carries the
    eponym as free text.
  phenotype_term:
    preferred_term: Paracusis of Willis
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients may describe improved hearing clarity in noisy environments.
    explanation: Describes the symptom this phenotype records.
- name: Schwartze Sign
  category: Otoscopic
  description: >-
    Reddish hue over the cochlear promontory seen through an otherwise normal
    tympanic membrane, produced by the hypervascular active focus. It is inconstant
    and its absence does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Schwartze sign (promontory hyperemia)
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This sign is inconsistently found in patients with otosclerosis and is not necessary for diagnosis.
    explanation: Supports the caveat that makes this an unreliable but real sign.
histopathology:
- name: Otospongiotic (Active) Focus with Vascular Proliferation
  description: >-
    Enlarged perivascular spaces, bone resorbed around vessels and replaced by
    fibrous tissue, osteoclastic giant cells and vascular proliferation. Osteoblast
    and osteoclast precursors, histiocytes and macrophages are seen on electron
    microscopy.
  finding_term:
    preferred_term: vascular proliferation within the otosclerotic focus
    term:
      id: NCIT:C35504
      label: Vascular Proliferation
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These areas of active disease are characterized by the presence of osteoclastic giant cells and vascular proliferation.
    explanation: States the two defining histologic features of the active focus.
- name: Sclerotic (Inactive) Focus of Dense Mineralized Bone
  description: >-
    The burnt-out end state of the lesion: dense mineralized bone replacing the
    resorbed otic-capsule bone.
  finding_term:
    preferred_term: dense sclerotic otosclerotic bone
    term:
      id: NCIT:C69309
      label: Sclerosis
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The otosclerosis focus may appear as dense mineralized bone (sclerosis) or active, well-vascularized bone (spongiotic).
    explanation: Names both the sclerotic and spongiotic appearances of the focus.
- name: Blue Mantles
  description: >-
    Basophilic (bluish on H&E) zones of recently remodeled bone bordering the focus,
    among the earliest histologic manifestations. No NCIT or HP term names this
    finding, so the descriptor is free text.
  finding_term:
    preferred_term: blue mantles (basophilic recently remodeled bone)
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One of the first histologic manifestations of otosclerosis is known as blue mantles, which are basophilic staining regions visualized after application of Hematoxylin and Eosin (H&E).
    explanation: Defines the finding and marks it as an early manifestation.
imaging_findings:
- name: Fissula Ante Fenestram Radiolucency on Temporal Bone CT
  modality: CT
  description: >-
    A hypodense (radiolucent) focus at the fissula ante fenestram, or pericochlear
    lucency in more extensive disease. High-resolution CT of the mastoid is the
    imaging modality of choice when stapes surgery is planned.
  located_in:
    preferred_term: bony otic capsule
    term:
      id: UBERON:0005411
      label: bony otic capsule
  spatial_extent: FOCAL
  evidence:
  - reference: PMID:33107781
    reference_title: "Pregnancy, Estrogen Exposure, and the Development of Otosclerosis: A Case-Control Study of 1196 Women."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Imaging criteria included radiolucency in the otic capsule at the fissula ante fenestram or surrounding the otic capsule.
    explanation: States the imaging criterion, here used as a diagnostic criterion in a population-based case ascertainment.
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mastoid HRCT is the imaging modality of choice for patients with a clinical indication for stapes surgery
    explanation: Supports the modality assignment.
inheritance:
- name: Autosomal dominant with reduced penetrance (familial otosclerosis)
  description: >-
    Around half to sixty per cent of patients have an affected relative, and in most
    such families transmission fits autosomal dominance with incomplete penetrance.
    The FOXL1 and SMARCA4 kindreds are the two families in which a segregating
    dominant variant has actually been identified.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In most families, the inheritance pattern is autosomal dominant with incomplete penetrance.
    explanation: States both the mode and the reduced penetrance recorded here.
- name: Polygenic susceptibility (non-familial otosclerosis)
  description: >-
    Sporadic disease behaves as a complex trait. A three-biobank GWAS meta-analysis
    of 3,504 cases and 861,198 controls found 27 genome-wide-significant loci and
    SNP-based heritability estimates of 0.15-0.27, confirming a polygenic
    architecture rather than a few high-impact genes.
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We confirm a polygenic basis to otosclerosis.
    explanation: The GWAS authors state the polygenic conclusion this record encodes.
genetic:
- name: OTSC linkage loci (OTSC1-OTSC10)
  association: >-
    Two decades of linkage mapping in multiplex families defined ten autosomal
    dominant OTSC intervals (OTSC1 15q25-qter, OTSC2 7q34-q36, OTSC3 6p22.3-p21.3,
    OTSC4 16q22.1-q23.1, OTSC5 3q22-q24, OTSC7 6q13-q16.1, OTSC8 9p13.1-q21.11,
    OTSC10 1q41-q44; OTSC6 and OTSC9 unpublished). The intervals are large — 10 to
    34 Mb — and, apart from FOXL1 mapping into the 16q24.1 region, none has yielded
    a causal gene. These loci are recorded here as genetic detail of one disease, not
    as clinical subtypes.
  relationship_type: UNKNOWN
  evidence:
  - reference: PMID:34633540
    reference_title: A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: multiplex families have been used to map ten autosomal dominant (OTSC) loci to large genomic intervals
    explanation: Establishes the number and nature of the OTSC intervals recorded here.
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, efforts to identify causative genes have produced inconsistent results, with insufficient evidence for most candidate genes
    explanation: Supports the statement that the intervals have largely not yielded causal genes.
- name: FOXL1
  association: >-
    A 15 bp coding deletion (rs764026385) in the C-terminus of FOXL1 co-segregates
    with autosomal dominant otosclerosis in a large Newfoundland family of English
    extraction and was found in a second unrelated case on a shared haplotype. The
    mutant protein is transcribed, translated and correctly nuclear, but loses its
    C-terminal alpha helix and all transcriptional activity, implying that wild-type
    FOXL1 normally restrains otic-capsule bone remodeling.
  gene_term:
    preferred_term: FOXL1
    term:
      id: hgnc:3817
      label: FOXL1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:34633540
    reference_title: A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family
    explanation: Reports the co-segregating variant that makes this a causative gene claim.
  - reference: PMID:34633540
    reference_title: A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure.
    explanation: >-
      The functional consequence was measured in reporter assays rather than in patients,
      so it is graded IN_VITRO separately from the segregation evidence above.
- name: SMARCA4
  association: >-
    Whole-exome sequencing plus linkage in a kindred with seven affected individuals
    identified a disease-causing SMARCA4 variant (p.E1548K), encoding a component of
    the PBAF chromatin-remodeling complex. Knock-in mice carrying the orthologous
    change are the only animal model that reproduces an otosclerosis-like phenotype.
  gene_term:
    preferred_term: SMARCA4
    term:
      id: hgnc:11100
      label: SMARCA4
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:37399313
    reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through genetic studies of kindred with seven individuals affected by apparent autosomal dominant otosclerosis, we identified a disease-causing variant in SMARCA4, encoding a key component of the PBAF chromatin remodelling complex."
    explanation: Reports the human genetic finding behind this CAUSATIVE assignment.
- name: MEPE
  association: >-
    MEPE encodes matrix extracellular phosphoglycoprotein, an osteocyte product with
    roles in both mineralization and osteoclast regulation. A rare frameshift variant
    (rs753138805), enriched in Finns, carries by far the largest effect of any
    otosclerosis allele reported to date and fine-maps as the most likely causal
    variant at its locus. MEPE protein is present in maturing and adult mouse otic
    capsule osteocytes.
  gene_term:
    preferred_term: MEPE
    term:
      id: hgnc:13361
      label: MEPE
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the chromosome 4 locus near the MEPE gene, the rare frameshift variant rs753138805 (EAF 0.3% in controls and 1.3% in cases) was the lead variant in the GWAS in FinnGen with an odds ratio of 21.5 (95% CI 9.6-48.4)"
    explanation: Gives the specific variant and effect size behind this susceptibility claim.
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our localization of MEPE protein within the maturing and adult otic capsule validates our GWAS finding."
    explanation: >-
      The expression validation was done by immunostaining mouse cochleae, so it is graded
      MODEL_ORGANISM separately from the human association above.
  notes: >-
    The frameshift is not otosclerosis-specific — the same variant also raises leg
    fracture risk, which the authors read as a systemic skeletal effect.
- name: TGFB1
  association: >-
    The most consistently replicated common susceptibility gene. An intronic variant
    (rs8105161) reached genome-wide significance in the three-biobank meta-analysis,
    and a British case-control study independently associated the coding variant
    rs1800472, most strongly among non-familial cases.
  gene_term:
    preferred_term: TGFB1
    term:
      id: hgnc:11766
      label: TGFB1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the only genome-wide significant association observed for the intronic TGFB1 variant rs8105161"
    explanation: Gives the genome-wide-significant TGFB1 association.
  - reference: PMID:29728750
    reference_title: Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence of an association between rs1800472 in TGFB1 and otosclerosis was found (p = 0.034), this association was strongest amongst non-familial cases (p = 0.011)."
    explanation: Independent replication in a different cohort, and locates the effect in non-familial disease.
- name: RELN
  association: >-
    Reelin was the first otosclerosis GWAS hit and remains associated in the largest
    meta-analysis, but replication has been erratic and a British study found the
    signal only in familial cases. Reelin has no known role in bone biology, which
    the field has repeatedly noted as a puzzle rather than a mechanism.
  gene_term:
    preferred_term: RELN
    term:
      id: hgnc:9957
      label: RELN
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the locus on chromosome 7, the strongest association was observed for variants in the second and third introns of RELN concordant with previous GWAS"
    explanation: Confirms the RELN association in the largest available meta-analysis.
  - reference: PMID:29728750
    reference_title: Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, a significant association (p = 0.0057) was detected between one RELN SNP (rs39399) and otosclerosis in familial patients."
    explanation: >-
      Supports a RELN association only in the familial stratum; the same study found none in
      the whole cohort, so it bears on the claim through a subgroup analysis.
  notes: >-
    The mechanistic gap is explicit in the literature: reelin's known function is
    neuronal migration, and no link to the bone dysregulation of otosclerosis has been
    demonstrated.
- name: CD109
  association: >-
    A GWAS lead variant in an intron of CD109 falls inside the previously mapped
    OTSC7 linkage region on 6q13-16.1, which is the only OTSC interval so far
    corroborated by association data. CD109 is a TGF-beta co-receptor and negative
    regulator, placing it on the same pathway as TGFB1.
  gene_term:
    preferred_term: CD109
    term:
      id: hgnc:21685
      label: CD109
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One locus (denoted by the lead variant rs4464751 in an intron of CD109) is a previously identified linkage locus (OTSC7, 6q13–16.1)"
    explanation: Establishes both the association and its coincidence with the OTSC7 interval.
- name: SERPINF1
  association: >-
    Contested. Whole-exome sequencing of familial cases reported six rare
    heterozygous SERPINF1 variants and reduced expression of the stapes-predominant
    SERPINF1-012 transcript, naming it the first otosclerosis gene. A subsequent
    resequencing study of 1,604 patients, 1,538 controls and 62 families found no
    enrichment, and specifically found the reported pathogenic p.Ala131Asp allele in
    more controls than patients. The evidence items below are deliberately kept as a
    SUPPORT/REFUTE pair rather than resolved.
  gene_term:
    preferred_term: SERPINF1
    term:
      id: hgnc:8824
      label: SERPINF1
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:27056980
    reference_title: Mutations and altered expression of SERPINF1 in patients with familial otosclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Six rare heterozygous SERPINF1 variants were found in seven patients in our familial otosclerosis cohort; three are missense mutations predicted to be deleterious to protein function.
    explanation: The original discovery finding that made SERPINF1 a candidate causal gene.
  - reference: PMID:30968248
    reference_title: Insufficient evidence for a role of SERPINF1 in otosclerosis.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study showed no enrichment of rare variants, stratified by type, in SERPINF1 in patients versus controls."
    explanation: A much larger resequencing study found no case-control enrichment, contradicting the discovery claim.
  - reference: PMID:30968248
    reference_title: Insufficient evidence for a role of SERPINF1 in otosclerosis.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "the c.392C > A (p.Ala131Asp) variant, previously reported as pathogenic, was identified in three patients and four controls, not replicating its pathogenic nature"
    explanation: Directly refutes the pathogenicity of the specific allele reported by the discovery study.
- name: COL1A1
  association: >-
    Type I collagen was the first candidate gene proposed, on the strength of its
    role in bone metabolism and its links to osteogenesis imperfecta and
    osteoporosis. Targeted replication in a British cohort found no association.
  gene_term:
    preferred_term: COL1A1
    term:
      id: hgnc:2197
      label: COL1A1
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:29728750
    reference_title: Evidence of distinct RELN and TGFB1 genetic associations in familial and non-familial otosclerosis in a British population.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No evidence of an association was detected with variants in COL1A1, FGF2, BMP2, and PPP2R5B."
    explanation: A powered replication attempt that failed to confirm the COL1A1 association.
- name: TNFRSF11B
  association: >-
    Candidate by function rather than by association: TNFRSF11B encodes
    osteoprotegerin, whose transcript is reduced in otosclerotic stapes, and
    homozygous TNFRSF11B variants cause juvenile Paget disease, which can itself
    cause hearing loss. No variant association with otosclerosis has been
    established.
  gene_term:
    preferred_term: TNFRSF11B
    term:
      id: hgnc:11909
      label: TNFRSF11B
  relationship_type: UNKNOWN
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "homozygous mutations in TNFRSF11B play a role in Paget’s disease, which may also lead to hearing loss"
    explanation: >-
      Supports candidate status only. The quoted sentence establishes a functional
      rationale by analogy with juvenile Paget disease, not an otosclerosis variant
      association, which is why relationship_type is UNKNOWN rather than SUSCEPTIBILITY.
prevalence:
- population: Populations of European descent
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 340.0
  rate_low: 300.0
  rate_high: 380.0
  notes: Clinical (symptomatic) otosclerosis, 0.30-0.38%.
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical otosclerosis has an estimated prevalence of 0.30–0.38% in populations of European descent
    explanation: Gives the population, measure and rate recorded here.
- population: Temporal bone autopsy specimens
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 2500.0
  notes: >-
    Histologic otosclerosis — otic-capsule bony overgrowth without clinical
    symptoms. Roughly an order of magnitude commoner than clinical disease, because
    only a minority of foci reach a site that fixes the stapes.
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologic otosclerosis without clinical symptoms is more frequent, with bony overgrowth observed in as many as 2.5% of temporal bone autopsy specimens"
    explanation: Gives the autopsy-series rate recorded here.
- population: Olmsted County, Minnesota, USA, 2015-2017
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.2
  notes: >-
    Rochester Epidemiology Project, 614 incident cases 1950-2017. The nadir of a
    steep decline from a 1970-74 peak of 18.5 per 100,000 person-years.
  evidence:
  - reference: PMID:32925838
    reference_title: "The Rise and Fall of Otosclerosis: A Population-based Study of Disease Incidence Spanning 70 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence rose from 8.9 per 100,000 person-years in the 1950s to a peak of 18.5 from 1970 to 1974. From this peak, the incidence significantly declined to 6.2 per 100,000 person-years by the early-1990s and reached a nadir of 3.2 from 2015 to 2017"
    explanation: Gives the modern incidence and the trajectory behind it.
progression:
- phase: Onset
  age_range: Second to fifth decade, most often the third
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Symptomatic otosclerosis most frequently occurs in working-age individuals between the second and fifth decades
    explanation: Gives the age band recorded for this phase.
- phase: Progression to bilateral disease
  notes: >-
    Onset is usually unilateral; most patients eventually have both ears involved.
  evidence:
  - reference: PMID:36653343
    reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Initial manifestation is often limited to one ear, but eventual bilateral disease is observed in 70–80% of cases
    explanation: Gives the unilateral-to-bilateral course recorded for this phase.
environmental:
- name: Persistent measles virus infection of the otic capsule
  description: >-
    The longest-standing environmental hypothesis. Measles virus RNA has been
    recovered from otosclerotic stapes footplates in many series and the incidence of
    otosclerosis fell steeply in the decades after mass measles vaccination. Other
    series using comparable RT-PCR methods have detected nothing at all. The
    hypothesis is therefore recorded here with both a supporting and a refuting
    primary study rather than as a settled cause.
  effect: Proposed trigger of otic-capsule remodeling; contested
  evidence:
  - reference: PMID:32968571
    reference_title: "Otosclerosis and Measles: Do Measles Have a Role in Otosclerosis? A Review Article."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The majority of the current literature supported the presence of the measles virus component in the otosclerotic stapes samples and its role in the etiopathogenesis of otosclerosis."
    explanation: >-
      A systematic review of 52 relevant articles reporting that most, though not all,
      support the association; graded OTHER because it is a synthesis, not primary data.
  - reference: PMID:32968571
    reference_title: "Otosclerosis and Measles: Do Measles Have a Role in Otosclerosis? A Review Article."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "On the contrary, five observational studies reported no evidence of the association."
    explanation: >-
      The same review counts the studies that found nothing; recorded as a separate
      REFUTE item because one evidence item cannot carry two opposite claims.
  influences_mechanisms:
  - target: Local Proinflammatory Cytokine Expression in the Otosclerotic Focus
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed route: persistent viral antigen in the focus drives local
      proinflammatory cytokine expression and osteoclast activation in a bone that is
      otherwise not remodeled.
    evidence:
    - reference: PMID:24676726
      reference_title: "Expression of TNF-α, OPG, IL-1β and the presence of the measles virus RNA in the stapes of the patients with otosclerosis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: The presence of measles virus RNA was noted in 80.3 % of otosclerotic stapes (49 out of 61) and 9.7 % of normal tissues (3 out of 31).
      explanation: >-
        A case-control detection difference in surgically removed stapes versus cadaveric
        controls. It shows association with the diseased tissue, not that the virus
        initiates remodeling, hence INDIRECT.
    - reference: PMID:24676726
      reference_title: "Expression of TNF-α, OPG, IL-1β and the presence of the measles virus RNA in the stapes of the patients with otosclerosis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The presence of TNF-α and IL-1β mRNA in the virus-positive stapes could be the result of viral antigen stimulation and may be a marker of inflammation the otosclerotic focus."
      explanation: >-
        States the proposed antigen-to-cytokine step of this link; the source's own hedging
        ("could be", "may be") is why it is graded INDIRECT.
    - reference: PMID:28971731
      reference_title: Absence of Measles Virus Detection from Stapes of Patients with Otosclerosis.
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "No sample was positive for any of 3 measles virus genes (H, N, and F). Measles virus RNA was not detected in any sample by real-time RT-PCR."
      explanation: >-
        A 93-patient cross-sectional study using real-time RT-PCR for three measles genes
        that found no virus at all, directly contradicting the detection studies.
  notes: >-
    No `exposure_term:` is bound. ECTO was searched (`runoak -i sqlite:obo:ecto`) for
    measles, virus and viral-exposure terms and returned nothing suitable; the ECTO
    virus-exposure branch does not carry a measles term, and no term beats a wrong
    term.
- name: Fluoride in drinking water
  description: >-
    Clinical otosclerosis has been reported to be commoner in low-fluoride areas,
    and sodium fluoride is proposed to neutralise proteolytic enzymes implicated in
    abnormal otic-capsule bone metabolism. This is the rationale behind fluoride
    supplementation as a medical therapy, which has never been supported by
    adequately designed trials.
  exposure_term:
    preferred_term: exposure to fluoride in drinking water
    term:
      id: ECTO:9000423
      label: exposure to fluoride
  effect: Proposed protective; epidemiological only
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: An epidemiological study on otosclerosis and fluoridated drinking water showed a higher prevalence of clinical otosclerosis in low-fluoride areas.
    explanation: >-
      An ecological prevalence comparison, reported second-hand by the task force; it
      supports an inverse association, not a demonstrated protective effect, hence INDIRECT.
  influences_mechanisms:
  - target: Focal Otospongiotic Bone Resorption
    environmental_effect: PROTECTS_AGAINST
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed mechanism for the inverse association: fluoride inactivates proteolytic
      enzymes that drive abnormal bone metabolism in the otic capsule.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: Sodium fluoride neutralizes proteolytic enzymes that can cause abnormal bone metabolism, such as the Diastrophic Dysplasia Sulfate Transporter
      explanation: >-
        States the proposed biochemical mechanism behind the protective claim; it is a
        mechanistic rationale rather than a measurement in otosclerotic bone, hence INDIRECT.
- name: Pregnancy and endogenous estrogen exposure
  description: >-
    A long-held clinical belief, resting on the roughly 2:1 female predominance and
    on reports of hearing deterioration around pregnancy. A population-based
    case-control study of 299 cases and 897 matched controls found no association
    with parity or with prior bilateral oophorectomy. It is recorded here as a
    refuted risk factor, with no mechanism link asserted.
  effect: No association demonstrated
  evidence:
  - reference: PMID:33107781
    reference_title: "Pregnancy, Estrogen Exposure, and the Development of Otosclerosis: A Case-Control Study of 1196 Women."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "These data do not support a relationship between endogenous estrogen exposure and development of otosclerosis."
    explanation: >-
      The study's own conclusion, from 1196 women, refutes the proposed estrogen risk
      factor.
  - reference: PMID:33107781
    reference_title: "Pregnancy, Estrogen Exposure, and the Development of Otosclerosis: A Case-Control Study of 1196 Women."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The odds ratio for the association of ≥1 delivery with otosclerosis was 1.16 (95% confidence interval [CI] 0.85-1.60; P = .35)."
    explanation: The null point estimate and confidence interval behind that conclusion.
  notes: >-
    No `exposure_term:` bound: this entry records the absence of an effect, and
    binding an ECTO exposure term would imply an asserted exposure-disease
    relationship the evidence refutes.
animal_models:
- name: Smarca4 E1548K knock-in mouse
  species: Mouse
  genotype: Smarca4+/E1548K (CRISPR-Cas9 knock-in of the orthologue of the human SMARCA4 p.E1548K variant)
  publication: PMID:37399313
  description: >-
    The only animal model of otosclerosis. Mice carrying the mouse orthologue of the
    human kindred's SMARCA4 variant are hearing-impaired on acoustic startle and
    auditory brainstem response testing, and micro-CT shows a highly irregular incus
    disrupting the ossicular chain.
  evidence:
  - reference: PMID:37399313
    reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We generated CRISPR-Cas9 transgenic mice carrying the human mutation in the mouse SMARCA4 orthologue.
    explanation: Documents how the model was made and that it carries the orthologue of the human kindred's allele.
  modeled_mechanisms:
  - target: Progressive Conductive Hearing Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse reproduces conductive-type hearing impairment arising from abnormal
      ossicular bone, from the same allele that causes the human disease.
    limitations: >-
      The murine lesion is an irregular incus interrupting the ossicular chain, not
      otosclerotic fixation of the stapes footplate at the oval window, and the paper
      reports no otic-capsule focus. Otosclerosis is elsewhere described as an
      exclusively human disorder, so this model reproduces the ossicular consequence
      rather than the otic-capsule dystrophy that defines the disease.
    readouts:
    - name: Auditory brainstem response and acoustic startle threshold
      target: Progressive Conductive Hearing Loss
      direction: DECREASED
      interpretation: >-
        Functional hearing loss in the mutant mice, the model's counterpart of the
        audiometric phenotype.
      evidence:
      - reference: PMID:37399313
        reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mutant Smarca4+/E1548K mice exhibited marked hearing impairment demonstrated through acoustic startle response and auditory brainstem response tests."
        explanation: Reports the hearing measurement behind this readout.
    - name: Micro-CT incus morphology and ossicular chain continuity
      target: Progressive Conductive Hearing Loss
      direction: ALTERED
      interpretation: >-
        Structural correlate: abnormal ossicular bone interrupting sound conduction.
      evidence:
      - reference: PMID:37399313
        reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Isolated ossicles of the auditory bullae of mutant mice exhibited a highly irregular structure of the incus bone, and their in situ micro-CT studies demonstrated the anomalous structure of the incus bone, causing disruption in the ossicular chain."
        explanation: Reports the micro-CT morphology behind this readout.
    evidence:
    - reference: PMID:37399313
      reference_title: SMARCA4 mutation causes human otosclerosis and a similar phenotype in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We demonstrate that otosclerosis can be caused by a variant in SMARCA4, with a similar phenotype of hearing impairment and abnormal bone formation in the auditory bullae in transgenic mice carrying the human mutation in the mouse SMARCA4 orthologue."
      explanation: >-
        The authors' own claim that the model is informative for the human disease, which
        is what the link asserts.
treatments:
- name: Stapedotomy
  description: >-
    The definitive treatment for fenestral otosclerosis with preserved cochlear
    reserve. A fenestra is made in the fixed footplate and a prosthesis is placed
    between the incus and the vestibule, bypassing the ankylosed stapes. Failure rate
    is around 6% and sensorineural loss is uncommon. Contraindications include an
    only-hearing ear, active Meniere disease, a persistent stapedial artery and
    tympanic membrane perforation.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: stapedotomy with stapes prosthesis placement
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: stapes prosthesis
        term:
          id: NCIT:C17598
          label: Prosthesis
  target_phenotypes:
  - preferred_term: Progressive conductive hearing impairment
    term:
      id: HP:0008607
      label: Progressive conductive hearing impairment
  target_mechanisms:
  - target: Stapes Footplate Fixation
    treatment_effect: BYPASSES
    description: >-
      The prosthesis restores sound transmission across a footplate that remains
      fixed; the otosclerotic focus itself is untouched, which is why surgery does not
      arrest the disease.
    evidence:
    - reference: PMID:36653343
      reference_title: "Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: stapedotomy surgery which replaces the fixed stapes bone with a mobile prosthesis
      explanation: States that the operation substitutes for the fixed stapes rather than treating the bone lesion.
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Stapedotomy is currently the most accepted surgical treatment for fenestral otosclerosis with good cochlear reserve.
    explanation: Establishes stapedotomy as the guideline-endorsed first-line surgical option.
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Stapedotomy is usually a safe procedure, with good results, few complications, and a failure rate of approximately 6%.
    explanation: Supports the safety and failure-rate statement in the description.
  notes: >-
    The device is carried as a `qualifiers` predicate-value pair because
    `TreatmentTerm` is rooted at NCIT:C25218 (Clinical Intervention or Procedure) and
    a device term cannot sit in that slot. NCIT has no term for a stapes prosthesis
    specifically, so the generic NCIT:C17598 (Prosthesis) is bound and the specificity
    is carried in `preferred_term`.
- name: Hearing aid amplification
  description: >-
    A well-indicated non-surgical alternative for patients who decline or are unfit
    for stapes surgery, and the recommended option after stapedotomy in severe mixed
    loss with a large residual air-bone gap. The guideline notes a worse cost-benefit
    ratio than surgery.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: hearing aid amplification
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  target_phenotypes:
  - preferred_term: Progressive conductive hearing impairment
    term:
      id: HP:0008607
      label: Progressive conductive hearing impairment
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The use of hearing aids is well indicated for the treatment of patients with otosclerosis. However, when compared with stapes surgery, the cost-benefit ratio is worse
    explanation: Task-force recommendation stating both the indication and its cost-benefit caveat.
  notes: >-
    Bound to the rehabilitation action rather than to the device, since NCIT:C183182
    (Hearing Aid) is equipment and is not reachable from NCIT:C25218; the device is
    kept queryable as a qualifier value.
- name: Cochlear implantation
  description: >-
    Reserved for advanced cochlear otosclerosis with profound deafness, on the same
    indications as any other cause of profound loss. Round-window and basal-turn
    ossification is a specific hazard, so MRI is required before implantation, and
    perimodiolar electrodes reduce facial nerve stimulation.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  context: Advanced cochlear otosclerosis with profound sensorineural deafness
  treatment_term:
    preferred_term: cochlear device implantation
    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: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with advanced otosclerosis are at increased risk of ossification of the round window membrane and basal turn, and the surgeon should order MRI as a mandatory test to prevent complications during the insertion of electrode array
    explanation: Supports both the indication in advanced disease and the ossification hazard described here.
  - reference: PMID:28874211
    reference_title: Audiological outcome of stapes surgery for far advanced cochlear otosclerosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stapes surgery is a suitable treatment option for patients with advanced otosclerosis, and should be considered mandatory, before offering cochlear implantation, for those with a demonstrable conductive component to their hearing loss."
    explanation: >-
      Constrains when cochlear implantation is the right operation: in advanced disease with
      a residual air-bone gap, stapes surgery comes first, and implantation is for the
      minority who gain little from it.
  - reference: PMID:39155792
    reference_title: Outcomes of Cochlear Implantation in Patients with Far-Advanced Otosclerosis
      Who Had Previously Undergone Stapes Surgery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Word recognition scores before surgery averaged 7.4% (at 70 dB) and increased
      significantly to 66.2% about 12 months after surgery.
    explanation: >-
      Quantifies the benefit this treatment is offered for, which the other two items
      constrain but do not measure. The cohort is 17 patients with far-advanced otosclerosis
      who had already had stapes surgery, so the figure describes implantation as the
      second operation rather than the first.
  notes: >-
    Sequencing matters here. In a series of 28 ears with thresholds above 80 dB — i.e.
    audiometrically implant-eligible — most did well with primary stapes surgery, 7% needed
    revision and only 10% went on to a cochlear implant.
- name: Sodium fluoride
  description: >-
    Used for decades on the rationale that fluoride inactivates proteolytic enzymes
    driving otic-capsule bone turnover. The 2023 task force grades the evidence as
    insufficient: no adequately designed study supports the indication.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium fluoride
      term:
        id: CHEBI:28741
        label: sodium fluoride
  target_mechanisms:
  - target: Focal Otospongiotic Bone Resorption
    treatment_effect: INHIBITS
    description: >-
      Intended to suppress the resorptive phase; the mechanism is a rationale rather
      than a demonstrated effect in otosclerotic bone.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: Fluoride ingestion may influence the prevalence of diseases with abnormal bone resorption.
      explanation: >-
        States the proposed target of the therapy. It is a general statement about bone
        resorption rather than a measured effect on otosclerotic foci, hence INDIRECT.
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Sodium fluoride has been used for decades to treat patients with otosclerosis. However, well-designed studies are lacking to support its indication (Insufficient evidence).
    explanation: >-
      The guideline finds the evidence insufficient, which cuts against the treatment's
      efficacy claim; recorded as REFUTE for that reason, not because harm was shown.
- name: Bisphosphonate therapy
  description: >-
    Tried as an antiresorptive for otospongiotic disease. Control imaging improves but
    clinical benefit is at most slight, and the task force grades the evidence as
    insufficient.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  target_mechanisms:
  - target: Focal Otospongiotic Bone Resorption
    treatment_effect: INHIBITS
    description: >-
      Antiresorptive suppression of the active otospongiotic phase; radiologic change
      is reported without a matching clinical effect.
    evidence:
    - reference: PMID:37647735
      reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: The use of bisphosphonates has shown radiologic improvement on control scans, but only slight clinical improvement in patients.
      explanation: >-
        Radiologic improvement of the focus is a surrogate for suppressed resorption, so it
        supports the mechanism indirectly while the same sentence limits the clinical claim.
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Higher-quality studies are still lacking to support their indication in patients with otosclerosis (Insufficient evidence).
    explanation: >-
      The guideline declines to endorse bisphosphonates, cutting against a clinical
      efficacy claim.
diagnosis:
- name: Pure-tone audiometry with Carhart notch and absent acoustic reflexes
  description: >-
    The diagnostic core: a conductive or mixed loss with an air-bone gap, a Carhart
    notch (an artefactual bone-conduction dip around 2 kHz produced by the fixed
    ossicular chain), absent stapedial reflexes and a type A or As tympanogram. In a
    typical case this constellation makes imaging largely unnecessary.
  evidence:
  - reference: PMID:33107781
    reference_title: "Pregnancy, Estrogen Exposure, and the Development of Otosclerosis: A Case-Control Study of 1196 Women."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical and audiologic assessments included the presence of a Carhart notch, absent acoustic reflexes, and a type A or As tympanogram."
    explanation: >-
      These are the criteria actually used to ascertain otosclerosis cases in a
      population-based study, so they document diagnostic practice rather than merely
      recommending it.
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: family history of otosclerosis, and successful stapes surgery in one of the ears gain little benefit from imaging
    explanation: Supports the statement that imaging adds little in a typical audiometrically classic case.
- name: High-resolution temporal bone CT
  description: >-
    Indicated before stapes surgery and when the presentation is atypical — mixed or
    sensorineural loss, fluctuating hearing, prior ear surgery or trauma, vestibular
    complaints, or a child with mixed loss (to exclude X-linked mixed deafness).
  diagnosis_term:
    preferred_term: high-resolution temporal bone computed tomography
    term:
      id: NCIT:C17204
      label: Computed Tomography
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mastoid HRCT is the imaging modality of choice for patients with a clinical indication for stapes surgery
    explanation: Establishes CT as the preoperative imaging modality of choice.
differential_diagnoses:
- name: Superior semicircular canal dehiscence
  description: >-
    A third-window lesion that produces an air-bone gap with an intact tympanic
    membrane and can be mistaken for otosclerosis. It is also an explicit
    contraindication to stapedotomy, so distinguishing it changes management.
  distinguishing_features:
  - Supranormal bone conduction thresholds and abnormal VEMP responses despite the air-bone gap.
  - Sound- and pressure-evoked vestibular symptoms, with dehiscence visible on CT.
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ménière’s disease or superior semicircular canal dehiscence are contraindications to stapedotomy (Insufficient evidence)."
    explanation: Establishes why this differential must be resolved before surgery.
- name: Meniere disease
  description: >-
    Overlaps otosclerosis in vestibular symptoms and fluctuating hearing, and is a
    relative contraindication to stapedotomy. Endolymphatic hydrops is itself seen in
    some patients with otosclerosis involving the spiral ligament, which blurs the
    boundary.
  distinguishing_features:
  - Episodic vertigo with fluctuating low-frequency sensorineural loss and aural fullness, rather than a stable air-bone gap.
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vestibular complaints should be investigated during clinical evaluation, as misdiagnosis can have significant implications on treatment outcomes, especially in patients with Ménière’s disease, an enlarged vestibular aqueduct, or superior semicircular canal dehiscence."
    explanation: Names the differentials that matter and says why getting them wrong changes outcomes.
notes: >-
  Lump/split: curated as a single Disease per the stub queue's lump review
  (stubs/Otosclerosis.yaml, entry_type DISEASE). The seeded stubs for otosclerosis 11
  (FOXL1) and otosclerosis 12 were folded into this entry. The numbered OTSC loci are
  mapped linkage intervals of one disease, not distinct clinical entities, and are
  recorded under `genetic:` rather than as `has_subtypes`. Histologic, clinical and
  cochlear otosclerosis are stages and distributions of the same lesion, so they are
  likewise handled as prevalence populations, phenotypes and progression rather than
  as subtypes.

  Module conformance was considered and declined for
  kb/modules/osteoporosis_bone_resorption.yaml. That module scopes itself to the
  osteoporoses and its chain terminates in net bone loss and skeletal fragility;
  otosclerosis is focal, confined to a bone that is normally not remodeled at all, and
  its endpoint is net sclerosis. The RANKL/osteoprotegerin step is a parallel use of
  the same axis rather than a conforming instance. The reasoning is repeated on the
  "Reduced Osteoprotegerin Restraint of Osteoclastogenesis" node so it is visible where
  the decision would be made.

  No `datasets:` block. `just discover-datasets Otosclerosis` returned no DIRECT
  candidate — every hit was GENE_ONLY, reached through SMARCA4, TGFB1 or RELN, and
  belonged to lung cancer, AML or macular degeneration studies. Those accessions
  resolve perfectly and are about other diseases, which is the Named Entity Confusion
  failure the dataset guidance warns about, so none was curated.

  Deep research: `just research-disorder perplexity Otosclerosis` failed three times
  with "Server disconnected without sending a response" on the default
  `sonar-deep-research` model, and `--fallback` did not engage because a runtime API
  error is not treated as a provider being unable to take work. The committed report
  is a Perplexity run on `sonar-reasoning-pro`. Its citations resolved 12/12, but 5 of
  7 quotes were near-miss paraphrases and 13 of 27 ontology labels named a different
  term (HP:0005117 offered as "Conductive hearing impairment" is in fact Elevated
  diastolic blood pressure), so no CURIE was taken from it — every binding here was
  selected independently with OAK.
stages:
- name: Histologic otosclerosis
  description: >-
    An otic-capsule focus that has not reached a site where it fixes the stapes or
    the round window, and so causes no symptoms. It is found only by sectioning
    temporal bones at autopsy, in roughly an order of magnitude more people than have
    clinical disease. Only some 12-15% of temporal bones with histologic otosclerosis
    show stapedial fixation.
  evidence:
  - reference: PMID:11568664
    reference_title: Prevalence of otosclerosis in an unselected series of temporal bones.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histologic otosclerosis is a disease process without clinical symptoms or manifestations that can be discovered only by sectioning of the temporal bone at autopsy."
    explanation: Defines this stage and how it is ascertained.
  - reference: PMID:11568664
    reference_title: Prevalence of otosclerosis in an unselected series of temporal bones.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some 12% to 15% of temporal bones with histologic otosclerosis have demonstrated stapedial fixation."
    explanation: Quantifies the fraction of histologic foci that progress to the clinical stage.
- name: Clinical otosclerosis
  description: >-
    A focus sited so that it interferes with stapes motion or the round window
    membrane, producing conductive hearing loss with tinnitus and sometimes vestibular
    symptoms. This is the stage at which patients present.
  evidence:
  - reference: PMID:11568664
    reference_title: Prevalence of otosclerosis in an unselected series of temporal bones.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical otosclerosis is otosclerosis at a site where it causes conductive hearing loss by interfering with the motion of the stapes or of the round window membrane."
    explanation: Defines this stage by lesion site rather than by lesion size.
- name: Cochlear (far-advanced) otosclerosis
  description: >-
    Extensive otic-capsule involvement reaching the cochlear endosteum. Sensorineural
    loss is added or predominates, thresholds may reach implant-eligible levels, and
    round-window or basal-turn ossification can complicate cochlear implantation.
  evidence:
  - reference: PMID:37647735
    reference_title: "Brazilian Society of Otology task force - Otosclerosis: evaluation and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cochlear otosclerosis refers to invasion of the cochlear endosteum with extensive involvement of the otic capsule, without stapes fixation, leading to NSHL, tinnitus, and vestibular symptoms."
    explanation: Defines this stage as the task force does.

mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:H80
      label: Otosclerosis
    mapping_predicate: skos:exactMatch
    mapping_source: ICD-10-CM
    notes: >-
      The ICD-10 subdivisions used to ascertain cases in biobank studies are H80.0
      (oval window, non-obliterative), H80.1 (oval window, obliterative), H80.2
      (cochlear), H80.8 (other) and H80.9 (unspecified).
📚

References & Deep Research

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 (3)

Record notes

Lump/split: curated as a single Disease per the stub queue's lump review (stubs/Otosclerosis.yaml, entry_type DISEASE). The seeded stubs for otosclerosis 11 (FOXL1) and otosclerosis 12 were folded into this entry. The numbered OTSC loci are mapped linkage intervals of one disease, not distinct clinical entities, and are recorded under `genetic:` rather than as `has_subtypes`. Histologic, clinical and cochlear otosclerosis are stages and distributions of the same lesion, so they are likewise handled as prevalence populations, phenotypes and progression rather than as subtypes. Module conformance was considered and declined for kb/modules/osteoporosis_bone_resorption.yaml. That module scopes itself to the osteoporoses and its chain terminates in net bone loss and skeletal fragility; otosclerosis is focal, confined to a bone that is normally not remodeled at all, and its endpoint is net sclerosis. The RANKL/osteoprotegerin step is a parallel use of the same axis rather than a conforming instance. The reasoning is repeated on the "Reduced Osteoprotegerin Restraint of Osteoclastogenesis" node so it is visible where the decision would be made. No `datasets:` block. `just discover-datasets Otosclerosis` returned no DIRECT candidate — every hit was GENE_ONLY, reached through SMARCA4, TGFB1 or RELN, and belonged to lung cancer, AML or macular degeneration studies. Those accessions resolve perfectly and are about other diseases, which is the Named Entity Confusion failure the dataset guidance warns about, so none was curated. Deep research: `just research-disorder perplexity Otosclerosis` failed three times with "Server disconnected without sending a response" on the default `sonar-deep-research` model, and `--fallback` did not engage because a runtime API error is not treated as a provider being unable to take work. The committed report is a Perplexity run on `sonar-reasoning-pro`. Its citations resolved 12/12, but 5 of 7 quotes were near-miss paraphrases and 13 of 27 ontology labels named a different term (HP:0005117 offered as "Conductive hearing impairment" is in fact Elevated diastolic blood pressure), so no CURIE was taken from it — every binding here was selected independently with OAK.

Review round 1: add cochlear implantation outcome evidence · 2026-09-09T23:12:12Z · View source

Acted on the non-blocking suggestion in the approving review of PR 11569. The deep-research report cited PMID:39155792 (far-advanced otosclerosis cochlear-implant cohort, n=17, all with prior stapes surgery) and its cache file was committed with the entry but nothing cited it, so the treatment carried indication and sequencing evidence with no outcome measure. Added a third SUPPORT item on the Cochlear implantation treatment quoting the results sentence verbatim from the cached record rather than from the report, since 5 of that report's 7 checked quotes were near-miss paraphrases. The explanation states that the cohort had already undergone stapes surgery, so the figure describes implantation as the second operation rather than the first. Snippet count went from 99/99 to 100/100 verified. Did not act on the review's second suggestion, that speech discrimination impairment be modeled as its own phenotype: it is a functional measure of the hearing-loss phenotypes already curated, the reviewer flagged it as a judgement call rather than a defect, and the HP term the report offered for it is one of the 13 mislabelled CURIEs.

Create: Otosclerosis · 2026-09-09T20:02:20Z · View source

Created kb/disorders/Otosclerosis.yaml (MONDO:0005349) from the lump-reviewed stub, which was deleted. Curated as a single Disease per stubs/Otosclerosis.yaml entry_type DISEASE: the numbered OTSC linkage loci and reported genes (FOXL1, SMARCA4, MEPE, TGFB1, RELN, CD109, SERPINF1, COL1A1, TNFRSF11B) are recorded under genetic:, not as has_subtypes; histologic/clinical/cochlear forms are recorded under stages:. Pathograph is an eight-node causal chain from reduced osteoprotegerin restraint, local TNF-alpha/IL-1beta expression and dysregulated TGF-beta signalling, through loss of otic-capsule remodeling quiescence, focal otospongiotic resorption and sclerotic replacement, to stapes footplate fixation (conductive loss) and cochlear endosteal involvement (mixed loss, vestibular symptoms). Module conformance to osteoporosis_bone_resorption was considered and declined - that module scopes to the osteoporoses and terminates in net bone loss, whereas otosclerosis is focal in a normally quiescent bone and ends in net sclerosis; the reasoning is recorded on the node and in entry notes. Contested claims are curated as SUPPORT/REFUTE pairs rather than resolved: SERPINF1 (PMID:27056980 discovery vs PMID:30968248 non-replication), persistent measles virus infection (PMID:24676726 detection vs PMID:28971731 non-detection), and pregnancy/estrogen exposure (PMID:33107781 null). Deep research: 'just research-disorder perplexity Otosclerosis' failed three times with 'Server disconnected without sending a response' on the default sonar-deep-research model; 'just dr_fallback=--fallback' did not engage because a runtime API error is not treated as the provider being unable to take work, and an explicit --fallback-provider chain did not engage either. The committed report research/Otosclerosis-deep-research-perplexity.md is a Perplexity run on sonar-reasoning-pro, so the requested provider did produce it. Its reference validation was 12/12 resolved, 0 unresolved, 2/7 quotes valid, needs_review true; term validation was 26/33 resolved with 13/27 labels naming a different term, so no CURIE was lifted from it and every binding was selected independently with OAK. No datasets: block was added because 'just discover-datasets Otosclerosis' returned no DIRECT candidate - all hits were GENE_ONLY lung cancer, AML and macular degeneration studies reached through SMARCA4/TGFB1/RELN. Validated: just validate (98/98 snippets verified), validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms and check-qualifier-terms-online, check-enum-values, check-stubs, check-environmental-evidence, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-reference-titles, and just validate-disorders.

Perplexity ▸
1. Disease Information
sonar-reasoning-pro 15 citations 2026-09-09T19:53:08.552245

1. Disease Information

Overview

Otosclerosis is a complex, multifactorial disease characterized by abnormal bone remodeling in the otic capsule, most commonly around the oval window, leading to fixation of the stapes and conductive hearing loss.[9][14] It is classically distinguished from “otospongiosis,” the active, vascular, spongiotic phase of lesions. Disease progression may involve the cochlea (far‑advanced otosclerosis), causing profound mixed or sensorineural loss.[2][4][15]

Recent narrative reviews emphasize its multifactorial nature (genetic, hormonal, possibly infectious) and its status as a major cause of adult‑onset conductive hearing loss.[9][14]

Key identifiers

(ontology/resource mapping based on standard use in the otology literature; codes given without links)

  • MONDO: MONDO:0005349 – Otosclerosis (otosclerosis of ear).
  • OMIM: OMIM #166800 – Otosclerosis 1 (familial).
  • Orphanet: ORPHA:668 – Otosclerosis.
  • ICD‑10: H80 (Otosclerosis), with subcodes (H80.0 otosclerosis involving oval window, etc.).
  • ICD‑11: AB41.0 – Otosclerosis.
  • MeSH: D010061 – Otosclerosis.
  • HPO (disease-level): HP:0008613 (Otosclerosis).

Synonyms / alternative names

  • Otospongiosis (often used for the active phase).
  • Stapedial otosclerosis / fenestral otosclerosis (oval-window–limited).
  • Cochlear otosclerosis / far‑advanced otosclerosis (FAO) when cochlea is involved.[2][4][15]

Evidence source type

Most information is derived from aggregated disease‑level resources and clinical series (case–control, cohort, and surgical outcome studies) rather than individual EHR analytics.[2][4][9][11][15]

2. Etiology

2.1 Disease causal factors

Genetic factors

Recent genetic work confirms that otosclerosis is a complex trait with polygenic susceptibility rather than a single-gene Mendelian disorder.[3][8][12]

  • A 2023 GWAS meta‑analysis of 3,504 cases and 861,198 controls across three population biobanks (FinnGen, EstBB, UK Biobank) identified 23 risk loci (p<5×10⁻⁸) and confirmed associations in RELN, TGFβ1, MEPE and the OTSC7 linkage region.[12]

    “We identify 23 novel risk loci … and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7).” (PMID: 36653343)[12]

  • A 2025 review summarizes that “linkage analysis has identified nine loci associated with monogenic forms of otosclerosis, yet the specific causative genes and variants remain elusive.”[3]
  • Early GWAS (2009) identified regions near RELN (chr7q22.1) and 11q13.1, with intronic SNP rs3914132 strongly associated with disease.[3]

These data support a polygenic, locus‑heterogeneous architecture with multiple moderate‑effect variants rather than a single dominant pathogenic gene.[3][8][12]

Non‑genetic factors (current understanding)

Evidence suggests contributions from:

  • Hormonal factors (female predominance, onset/exacerbation during pregnancy) – mainly clinical observational data.
  • Possible infectious/immune factors (historical measles virus association), although recent work has not confirmed a single obligatory pathogen.
  • Mechanical/audiologic stress and generalized bone‑metabolism influences (e.g., association with other bone diseases) – limited data.

Most of these are supported by older clinical and pathologic series; robust 2023–2024 mechanistic data remain sparse.

2.2 Risk factors

Genetic risk

  • TGFβ1 intronic variant rs8105161 has been confirmed as a major risk allele, emerging as the strongest association in a meta‑analysis.[3][12]

    “A meta-analysis of GWAS studies … confirmed the association between TGFβ1 and otosclerosis, identifying the intronic variant rs8105161 as the strongest.”[3]

  • RELN region variant rs3914132 near RELN is strongly associated.[3]
  • Multiple new loci (23) identified in the 2023 GWAS suggest additional candidate genes involved in bone remodeling and extracellular matrix (e.g., MEPE).[12]
  • Targeted resequencing in familial and sporadic patients has further supported roles for RELN, TGFβ1, MEPE and other loci, but no high‑penetrance coding variant has been established.[10]

    “The most recent GWAS … resulted in the identification of 18 loci associated with otosclerosis, including genes that were previously associated with otosclerosis, e.g., RELN, TGFβ1 and MEPE.” (PMCID: PMC9737413)[10]

Environmental / demographic risk

From clinical reviews and surgical series:

  • Sex: Otosclerosis is more common in women than men, with ratios often ~2:1 in surgical cohorts.[9][14]
  • Age: Typical onset is young–adult to mid‑adult (second to fourth decade).[9][14]
  • Family history: Positive family history is common, and familial clusters have been used in linkage studies.[3][8][10]
  • Ethnicity: Higher prevalence is reported in populations of European ancestry compared with some non‑European groups, supported indirectly by biobank GWAS composition.[12]

Robust associations with specific toxins, occupational exposures, or lifestyle factors have not been consistently demonstrated in recent literature.

2.3 Protective factors

No clearly established protective genetic alleles or environmental factors have been identified in recent GWAS and resequencing work.[3][10][12] Most studies focus on risk loci; protective or resilience alleles remain largely unexplored.

2.4 Gene–environment interactions

The 2022–2023 genetic literature emphasizes complex inheritance and polygenic risk but does not provide definitive gene–environment interaction models.[3][8][12] For example, the 2022 review notes that even with multiple GWAS signals, “causative genes for otosclerosis remain largely unidentified,” implying that non‑genetic factors may be required for lesion formation.[8] Experimental G×E otology studies (e.g., hormonal modulation in genetically susceptible individuals) are sparse.

3. Phenotypes

3.1 Core clinical phenotypes

Key phenotypes (with suggested HPO terms):

  1. Progressive conductive hearing loss
  2. Type: symptom / clinical sign.
  3. Characteristics: adult‑onset, slowly progressive, often bilateral; severity variable from mild to severe.
  4. HPO: HP:0005117 (Conductive hearing impairment).
  5. Common: otosclerosis is a leading cause of adult‑onset conductive loss.[9][14]

  6. Quality of life: significantly impacts communication, employment, and social functioning; cochlear implant studies demonstrate large gains in speech recognition and subjective QoL when hearing loss is treated.[6][13]

  7. Mixed hearing loss in far‑advanced otosclerosis (FAO)

  8. Phenotype: mixed (conductive + sensorineural) hearing loss.
  9. HPO: HP:000 Mixed – HP:000 Mixed hearing impairment (e.g., HP:000 Mixed).

  10. Evidence: FAO cohorts show preoperative air‑conduction thresholds ~100–110 dB and minimal bone conduction, indicating profound mixed or SN loss.[6][15]
    > “Average preoperative hearing thresholds were 108 dB HL for air conduction and were at the limit of the audiometer for bone conduction.” (PMID: 39155792)[6]

  11. Tinnitus

  12. Frequent symptom; variable severity.
  13. HPO: HP:0000360 (Tinnitus).

  14. Reported in many clinical series and reviews.[9][14]

  15. Vertigo / imbalance (less common)

  16. HPO: HP:0002321 (Vertigo).

  17. Typically mild or transient, more common with cochlear involvement or post‑surgery than in pure fenestral disease.[9][14]

  18. Speech discrimination impairment

  19. HPO: HP:0004305 (Impaired speech discrimination).
  20. Markedly impaired in FAO; CI and stapes surgery series track word recognition scores as key functional endpoints.[2][6][11][13][15]

3.2 Phenotype characteristics (age, severity, progression)

  • Age of onset: most often young adulthood (20–40 years), though subclinical lesions may precede symptoms.[9][14]
  • Severity: ranges from mild conductive deficit to profound mixed loss in FAO; severity correlates with anatomical spread (fenestral vs cochlear).[2][6][15]
  • Progression: generally progressive and insidious; FAO represents end‑stage cochlear involvement.[2][4][15]
  • Frequency among affected individuals: conductive hearing loss is nearly universal; tinnitus occurs in a substantial subset; vertigo is less frequent.[9][14]

3.3 Quality of life impact

CI outcome studies demonstrate large QoL gains:

  • In a 2024 FAO CI cohort, word recognition improved from 7.4% pre‑operative to 66.2% ~12 months post‑implant.[6]

    “Word recognition scores before surgery averaged 7.4% … and increased significantly to 66.2% about 12 months after surgery.”[6]

  • Contemporary CI series report post‑operative disyllabic and sentence recognition scores of 68–74% and 75–92.5%, respectively, in advanced otosclerosis, reflecting major improvements in everyday communication.[13]

    “Otosclerotic CI recipients show post-operative mean disyllabic word and sentence recognition scores between 68–74.2% and 75–92.5%, respectively.”[13]

  • A 2019 FAO management series reported that all patients achieved satisfactory face‑to‑face communication and 90% could use the telephone after stapedotomy or CI.[15]

    “Overall, all patients had satisfactory face-to-face communication and 90% could use telephone.”[15]

These outcomes indicate severe baseline disability with high potential for functional restoration with appropriate intervention.[2][6][11][13][15]

4. Genetic / Molecular Information

4.1 Causal and risk genes

Key loci and candidate genes (complex trait)

  • RELN (Reelin) – near the chr7q22.1 GWAS locus (rs3914132).[3][8][12]
  • TGFβ1 (Transforming growth factor beta 1) – intronic variant rs8105161 strongly associated; key regulator of bone remodeling.[3][8][12]
  • MEPE (Matrix extracellular phosphoglycoprotein) – bone matrix protein implicated by GWAS loci.[10][12]
  • OTSC linkage loci (OTSC1–OTSC10) – mapped in familial series, but specific genes remain mostly unidentified.[3][8]

These genes participate in extracellular matrix organization, bone formation, and remodeling, fitting the pathophysiologic theme of aberrant otic capsule bone turnover.[3][8][12]

Suggested HGNC/GO mappings:

  • RELN (HGNC:9955) – GO:0007269 (neurotransmitter secretion), GO:0007417 (central nervous system development); possible role in inner ear microarchitecture.
  • TGFB1 (HGNC:11766) – GO:0001501 (skeletal system development), GO:0030509 (BMP signaling).
  • MEPE (HGNC:7005) – GO:0001503 (ossification), GO:0001501 (skeletal system development).

4.2 Pathogenic variants and classification

GWAS‑identified SNPs (e.g., rs8105161 in TGFβ1, rs3914132 near RELN) are risk alleles, not high‑penetrance Mendelian pathogenic variants.[3][12] They are common and have small to moderate effect sizes typical of complex traits.[3][8][12]

  • Variant type: intronic/non‑coding, affecting regulation rather than coding sequence.[3][12]
  • Origin: germline; no somatic otosclerosis variants have been described.[3][8][10]
  • Population frequency: by definition common enough to be detected in GWAS; specific allele frequencies are reported in gnomAD/biobank data but not detailed in the cited abstracts.[12]
  • ACMG classification: risk alleles in complex disease; not “pathogenic” in Mendelian sense.

Targeted resequencing studies identify rare coding variants in candidate genes, but their pathogenic status remains mostly “variant of uncertain significance” (VUS) due to limited segregation and functional data.[10]

4.3 Modifier genes, epigenetics, chromosomal abnormalities

  • Modifier genes: multiple GWAS loci likely act as modifiers of susceptibility and severity; RELN/TGFβ1/MEPE may be considered modifying elements in a broader polygenic network.[3][8][10][12]
  • Epigenetic changes: recent reviews call for epigenomic work, but specific otosclerosis methylation or histone-modification signatures have not yet been robustly reported.[3][8]
  • Chromosomal abnormalities: large‑scale structural variants (aneuploidy, translocations) are not a recognized cause of otosclerosis; GWAS signals are primarily SNP‑based.[12]

5. Environmental Information

Recent high‑throughput studies focus on genetics; large-scale environmental and toxicologic association studies are lacking.[3][8][12]

  • Toxins, radiation, pollution: no consistent link established in recent otosclerosis literature.
  • Lifestyle: smoking, diet, and general lifestyle factors have not shown strong, reproducible associations in modern datasets; any effects are likely small.
  • Infectious agents: older work implicated measles virus antigen in otic capsule lesions, but contemporary consensus is that otosclerosis cannot be explained by a single infectious agent; modern GWAS strengthens the complex genetic model.[3][8][12]

6. Mechanism / Pathophysiology

6.1 Ordered causal chain (conceptual)

  1. Polygenic susceptibility variants in bone‑remodeling and extracellular‑matrix genes (e.g., RELN, TGFβ1, MEPE) lead to dysregulated otic capsule bone turnover under normal mechanical and hormonal conditions.[3][8][12]
  2. Dysregulated bone remodeling results in formation of spongiotic, vascular otosclerotic foci (otospongiosis) in the otic capsule, especially near the oval window (fenestral region).[9][14]
  3. Expansion and sclerosis of lesions around the stapes footplate lead to mechanical fixation of the stapes and impaired ossicular chain mobility, causing conductive hearing loss.[9][14]
  4. When lesions extend into the cochlear endosteum and perilymphatic space, they result in secondary cochlear damage (hair cell/spiral ligament/stria vascularis injury), producing sensorineural components and far‑advanced otosclerosis.[2][4][6][15]
  5. Chronic auditory deprivation and reduced speech audibility lead to impaired speech discrimination and substantial communicative disability.[2][6][11][13][15]
  6. Surgical correction (stapedotomy/stapedectomy or cochlear implantation) results in partial or near‑complete restoration of sound transmission and speech recognition, thereby reversing much of the functional deficit.[1][2][5][6][11][13][15]

Steps 1–2 and 4 involve mechanistic inference based on histopathology and genetic association rather than direct experimental proof in humans; steps 3 and 6 are well demonstrated clinically.

6.2 Molecular pathways

Genetic and functional annotations implicate several pathways:

  • TGFβ signaling and bone remodeling
  • TGFβ1 variants and expression changes point to altered signaling in osteoblasts/osteoclasts, affecting otic capsule bone homeostasis.[3][8][12]

  • Suggested GO terms: GO:0001503 (ossification), GO:0001501 (skeletal system development), GO:0030509 (BMP signaling pathway).

  • Extracellular matrix and mineralization

  • MEPE and other matrix proteins suggest disturbed mineralization and matrix turnover.[10][12]

  • GO:0030198 (extracellular matrix organization), GO:0001504 (bone mineralization).

  • General bone‑metabolism cascades (RANKL/RANK/OPG, Wnt) are hypothesized from general bone biology but not yet directly mapped with omics in otosclerosis.

6.3 Cellular processes and protein dysfunction

  • Aberrant osteoclast and osteoblast activity in the otic capsule (bone resorption and formation cycles) results in spongiotic and sclerotic lesions.
  • GO:0030278 (regulation of ossification), GO:0045667 (regulation of osteoblast differentiation).
  • Vascular invasion of normally avascular otic capsule bone during active lesions (otospongiosis) is seen histologically, implying altered angiogenesis and matrix turnover.[9][14]
  • No single misfolded or aggregated protein has been established; dysfunction is at the tissue/organ level (bone matrix) rather than classic proteinopathy.

6.4 Immune system and tissue damage

  • Historical presence of immune cells and measles antigen in lesions suggested an immune component; current consensus is that immune involvement is secondary/modulatory rather than primary.[3][8]
  • Tissue damage is mechanical (stapes fixation) plus potential cochlear damage (hair cell loss, spiral ligament/stria vascularis changes) inferred from audiometric patterns in FAO.[2][6][15]
  • Suggested GO:0001837 (epithelial–mesenchymal transition in bone), GO:0006954 (inflammatory response – tentative).

6.5 Molecular profiling and advanced technologies

There are, as of 2022–2024, no large‑scale single‑cell or spatial transcriptomic studies specifically mapping otosclerotic lesions; reviews explicitly identify this as a gap and argue that “omics” work is needed to clarify causal genes and pathways.[3][8][10][12]

Suggested cell types (CL terms):

  • CL:0000134 – Osteoblast.
  • CL:0000092 – Osteoclast.
  • CL:0000007 – Fibroblast of connective tissue.
  • CL:0000001 – Neuron (cochlear nerve fibers).
  • CL:0000004 – Sensory hair cell (inner ear).

7. Anatomical Structures Affected

7.1 Organ and system level

Primary organs:

  • Temporal bone / otic capsule.
  • UBERON:0001756 (otic capsule).
  • Middle ear (oval window, stapes).
  • UBERON:0001686 (stapes).
  • Inner ear (cochlea) in FAO.
  • UBERON:0001825 (cochlea).

Body system: auditory component of the nervous system (special sensory system).

Secondary involvement: central auditory pathways are functionally affected by chronic auditory deprivation, though not structurally diseased.

7.2 Tissue and cell level

  • Bone (lamellar bone of otic capsule) – connective tissue.
  • Vascular connective tissue within lesions (otospongiosis).
  • Sensory epithelium (organ of Corti), spiral ligament, and stria vascularis in cochlear otosclerosis (inferred from audiologic phenotype).

7.3 Subcellular level

No specific subcellular compartment defect (e.g., mitochondrial pathology) is established; disturbance is in tissue‑level bone remodeling and extracellular matrix.

7.4 Localization and lateralization

  • Lesions are often bilateral but can be asymmetric; many patients present with bilateral conductive loss.[9][14]
  • Fenestral otosclerosis: localized around oval window/stapes footplate.
  • Cochlear otosclerosis: lesions encroaching on cochlear endosteum and perilymphatic spaces.[2][6][15]

8. Temporal Development

Onset and pattern

  • Typical onset: young adulthood (20–40 years), insidious and chronic.[9][14]
  • Disease course: progressive; FAO reflects end‑stage cochlear involvement.[2][6][15]
  • Duration: chronic, often lifelong if untreated.

Stages

Clinically, stages are often conceptualized:

  1. Early fenestral disease – mild–moderate conductive loss.
  2. Advanced fenestral disease – severe conductive loss.
  3. Cochlear involvement (FAO) – profound mixed/SN loss.[2][6][15]

Remission or spontaneous regression is rare; progression may slow but generally does not reverse.

9. Inheritance and Population

Inheritance pattern

  • Family aggregation and linkage mapping support an autosomal‑dominant pattern with incomplete penetrance in many families, but polygenic risk in the general population.[3][8][10][12]
  • The 2022 review describes otosclerosis as “finally catching up with other complex traits,” emphasizing multifactorial inheritance.[8]

Penetrance and expressivity

  • Incomplete penetrance: many carriers of risk alleles do not develop clinical disease.[3][8][12]
  • Variable expressivity: severity and pattern (fenestral vs cochlear) differ among affected family members.

Epidemiology (overview)

Modern biobanks provide large numbers of cases (3,504 in 2023 GWAS) but do not, in the cited abstracts, give explicit global prevalence figures.[12] Historically, prevalence estimates in European populations have ranged around 0.3–0.4%, with lower rates in some non‑European groups; these values are derived from older epidemiological studies rather than the recent GWAS abstracts.

Demographics

  • Sex ratio: female predominance is noted in clinical and surgical series.[9][14]
  • Age distribution: adult‑onset disease, rarely symptomatic in childhood.[9][14]
  • Ethnicity/geography: GWAS cases predominantly from European‑ancestry biobanks (Finland, Estonia, UK), consistent with higher recognition in these populations.[12]

10. Diagnostics

10.1 Clinical tests

Standard diagnostic approach (summarized from reviews and surgical series):

  • Audiometry
  • Pure‑tone audiometry showing conductive or mixed loss, often with characteristic Carhart notch at 2 kHz.

  • FAO cohorts show preoperative air‑conduction thresholds ~100–110 dB HL and essentially absent bone conduction, indicating profound loss.[2][6][15]

  • Speech audiometry

  • Word recognition scores are key for decision‑making between stapedotomy and CI; FAO patients often have very low preoperative scores (e.g., 7.4%) which improve substantially after CI.[6][11][13][15]

  • Imaging

  • High‑resolution temporal bone CT can demonstrate fenestral and cochlear otosclerotic foci, guide surgical planning, and identify cases where stapes surgery is unlikely to help (e.g., severe cochlear obstruction).[4][13]

  • Tuning‑fork tests and clinical examination

  • Weber and Rinne tests show conductive pattern in fenestral disease.

Histopathologic diagnosis is usually post‑mortem or in rare biopsy situations; routine diagnosis relies on audiology and imaging.[9][14]

Suggested LOINC concepts: pure‑tone audiometry, speech discrimination testing.

10.2 Genetic testing

Because otosclerosis is a complex trait with GWAS‑identified risk alleles rather than a monogenic disorder, routine clinical genetic testing is not yet standard.[3][8][12]

  • Single‑gene tests: not established, as no single causative gene is known.
  • Gene panels / WES / WGS: used in research (linkage, resequencing, GWAS), but not recommended as first‑line clinical tests for typical otosclerosis.[3][8][10][12]

10.3 Clinical criteria and differential diagnosis

Clinical diagnosis combines:

  • Progressive conductive/mixed hearing loss.
  • Normal tympanic membrane and middle ear on otoscopic exam.
  • Characteristic audiometric pattern.
  • Absence of middle‑ear effusion, ossicular discontinuity, cholesteatoma, or superior canal dehiscence (ruled out by exam and CT).[9][14]

Differential diagnosis includes:

  • Congenital ossicular malformations.
  • Chronic otitis media with effusion.
  • Ossicular chain discontinuity.
  • Tympanosclerosis.
  • Superior canal dehiscence syndrome.

10.4 Screening

No population‑wide screening programs exist; case‑finding is based on symptomatic presentation and audiologic evaluation. Family members of patients with strong family histories may be advised to have audiometry, but this is not formal screening.

11. Outcome / Prognosis

11.1 Survival and mortality

Otosclerosis is not life‑limiting; survival and life expectancy are essentially normal. The disease is important for morbidity (hearing disability) rather than mortality.

11.2 Morbidity, disability and QoL

  • Stapes surgery and CI both yield major improvements; series report high rates of useful speech discrimination and telephone use post‑treatment.[2][6][11][13][15]

    “Six FAO patients benefited well from stapedotomy with an average of 5.9-decibel air-bone gap and 86% median speech discrimination…. Median speech discrimination score of CI patients was 78.4%.” (PMCID: PMC7162605)[15]
    “Cochlear implantation leads to a statistically greater and consistent improvement in speech recognition scores.”[1]

  • Nevertheless, a subset of patients obtain limited benefit from stapes surgery and require CI.[2][4][11]

11.3 Disease course and complications

Main complications relate to:

  • Progressive hearing loss and communication disability if untreated.
  • Surgical complications:
  • Stapes surgery has variable outcomes and small risk of worsening hearing or vertigo.[2][4][11][15]
  • CI in otosclerosis shows a relatively low rate of complications and hearing loss after surgery in meta‑analysis.[7]
    > “Meta-analysis … showed that CI had significant lower rate of any postoperative complications in patients with far-advanced otosclerosis… and significant lower rate of hearing loss after surgery.” (PMCID: PMC9813143)[7]

Prognostic factors include baseline word recognition, extent of cochlear involvement on CT, and prior stapes surgeries.[4][6][11][13][15]

12. Treatment

12.1 Pharmacotherapy

No drug therapy has proven capable of reversing otosclerotic lesions or restoring hearing; pharmacologic agents (e.g., fluoride, bisphosphonates) have been explored historically but are not standard of care in recent guidelines.

12.2 Surgical and interventional treatment

Stapes surgery (stapedotomy/stapedectomy)

  • Indicated for fenestral disease with a substantial conductive component.
  • A 2017 FAO series reported that “the audiological outcome for most patients who underwent primary stapes surgery was good,” with only 7% requiring revision and 10% later receiving CI.[2]

    “Stapes surgery is a suitable treatment option for patients with advanced otosclerosis, and should be considered mandatory, before offering cochlear implantation, for those with a demonstrable conductive component to their hearing loss.” (PMID: 28874211)[2]

  • A 2023 FAO series found success rates of stapedotomy on tonal audiometry ranging from 36–100%, with verbal recognition rates 38–75%, slightly lower than CI results.[11]

    “The literature shows that the success rate of stapedotomy in FAO ranges from 36 to 100% … these data are slightly lower than the results obtained with cochlear implants.” (PMCID: PMC10000942)[11]

Cochlear implantation (CI)

  • CI is preferred for FAO or when stapes surgery has failed or is unlikely to help due to cochlear obstruction.[1][4][6][7][11][13][15]
  • Systematic review and meta‑analysis (2016) concluded:

    “Cochlear implantation leads to significantly better speech recognition scores than stapedotomy (P<.0001)… Stapedotomy is not universally effective; however, it yields good results comparable to cochlear implantations in at least half of patients.” (PMID not given in snippet)[1]

  • A 2024 FAO cohort reported word recognition improvement from 7.4% to 66.2% at 12 months.[6]
  • Contemporary review:

    “Cochlear implantation in advanced otosclerosis results in consistent, excellent auditory outcomes with improvement in both objective speech recognition scores and subjective quality of life measures.”[13]

  • Meta‑analysis indicates CI has lower rates of postoperative complications and hearing loss than stapes surgery in FAO.[7]

Combined or staged strategies

  • Some authors advocate stapedotomy first in FAO with residual conductive components, with CI reserved as a backup.[2][4][11][15]

    “Bilateral stapedotomy and wearing hearing aid is an effective and cost-effective solution… Should stapedotomy fail, cochlear implantation is always a successful back-up option.”[15]

Suggested NCIT terms:

  • NCIT:C51548 – Stapedectomy.
  • NCIT:C51546 – Cochlear Implantation.
  • NCIT:C15233 – Hearing Aid.

12.3 Advanced therapeutics, experimental treatments

No gene, cell, or RNA‑based therapies are currently in clinical use for otosclerosis; ongoing research focuses on understanding genetic architecture and bone‑remodeling pathways.[3][8][10][12]

12.4 Treatment outcomes and strategy

Strategy

  • Fenestral/typical otosclerosis: stapes surgery + hearing aids, with high success rates.[2][11][15]
  • Far‑advanced/cochlear otosclerosis: CI often yields more consistent speech recognition; stapes surgery may be attempted first if a substantial conductive component exists.[1][2][4][5][6][7][11][13][15]
  • Personalized approach: audiometric profile, imaging, prior surgeries, and patient preferences guide choice.

13. Prevention

Because otosclerosis is largely a complex genetic bone‑remodeling disorder with no known modifiable major risk factors, prevention strategies are limited.

  • Primary prevention: no established measures.
  • Secondary prevention: early diagnosis and timely stapes surgery or CI to prevent prolonged auditory deprivation and its psychosocial consequences.[2][6][11][13][15]
  • Tertiary prevention: rehabilitation with hearing aids, CI, and auditory training to maximize functional adaptation.

Genetic counseling may be offered to families with strong clustering, explaining complex inheritance and incomplete penetrance, but no formal carrier screening or prenatal diagnosis protocols exist.

14. Other Species / Natural Disease

The cited 2022–2024 human GWAS and treatment literature does not discuss natural otosclerosis‑like disease in animals; otosclerosis is currently considered a primarily human condition.[3][8][12] Older comparative pathology references mention conductive hearing loss in some domestic animals, but specific “otosclerosis” analogs are not well characterized.

15. Model Organisms

Otosclerosis lacks classic, widely used animal models that faithfully recapitulate the human otic capsule bone remodeling lesion.

  • Genetic mouse models targeting TGFβ or bone‑matrix genes exist for bone research generally, but not specifically validated as otosclerosis models.[3][8]
  • Reviews emphasize that future work should use animal and in vitro models to test candidate genes and pathways identified by GWAS.[3][8][10][12]

Thus, at present, the primary “models” are human clinical cohorts and temporal bone histopathology, rather than formal experimental organisms.

Evidence Source Types (summary)

  • Human clinical: surgical outcome series, audiologic cohorts, and imaging studies (e.g., FAO series and CI vs stapes comparisons).[1][2][4][5][6][7][11][13][15]
  • Human genetic: GWAS meta‑analyses, linkage studies, and targeted resequencing.[3][8][10][12]
  • In vitro / animal: general bone biology and TGFβ/ECM pathways (not otosclerosis‑specific).
  • Computational: GWAS fine‑mapping, biobank meta‑analysis, and variant prioritization.[10][12]

This synthesis reflects current understanding up to approximately 2024, emphasizing the shift from a predominantly clinical–surgical view of otosclerosis toward a complex, polygenic bone‑remodeling disorder with emerging but still incomplete molecular definition.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 12
Resolved 12
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 7
Quoted claims found in source 2
Quoted claims not found in source 5
References weighed for topical relevance 12
On topic 8
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

4 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:36653343: "We identify 23 novel risk loci … and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7)."
  • closest text in source: "We identify 23 novel risk loci (p < 5 × 10-8) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7)"
  • PMC:PMC9737413 (abstract only): "The most recent GWAS … resulted in the identification of 18 loci associated with otosclerosis, including genes that were previously associated with otosclerosis, e.g., RELN, TGFβ1 and MEPE."
  • closest text in source: "Recently, a genome-wide association study (GWAS) identified 15 novel risk loci and replicated the regions of three previously reported candidate genes"
  • PMC:PMC7162605 (abstract only): "Six FAO patients benefited well from stapedotomy with an average of 5.9-decibel air-bone gap and 86% median speech discrimination…. Median speech discrimination score of CI patients was 78.4%."
  • closest text in source: "RESULTS: Six FAO patients benefited well from stapedotomy with an average of 5.9-decibel (dB) air-bone gap and 86% median speech discrimination"
  • PMC:PMC9813143 (abstract only): "Meta-analysis … showed that CI had significant lower rate of any postoperative complications in patients with far-advanced otosclerosis… and significant lower rate of hearing loss after surgery."
  • closest text in source: "OBJECTIVE: This study is to compare the hearing outcomes and complications of stapes surgery and cochlear implantation (CI) in patients with far-advanced otosclerosis (FAO)"
  • PMC:PMC10000942 (abstract only): "The literature shows that the success rate of stapedotomy in FAO ranges from 36 to 100% … these data are slightly lower than the results obtained with cochlear implants."
  • closest text in source: "Despite being based on a small sample of patients, our results suggest that stapedotomy plus hearing aids could improve the auditory capacities of patients with FAO independent of their auditory thresholds at T0"

Term Validation

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

Outcome Count
Terms checked 33
Resolved 26
Unresolved (possible confabulation) 2
Obsolete 1
Unverifiable 4
Terms whose name was checked 27
Terms named correctly 11
Terms named as a different term 13
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0005117 (1 mention) - the report calls it "Conductive hearing impairment"; HP calls it Elevated diastolic blood pressure
  • HP:0004305 (1 mention) - the report calls it "Impaired speech discrimination"; HP calls it Involuntary movements
  • GO:0001504 (1 mention) - the report calls it "bone mineralization"; GO calls it neurotransmitter uptake
  • CL:0000134 (1 mention) - the report calls it "Osteoblast"; CL calls it mesenchymal stem cell
  • CL:0000007 (1 mention) - the report calls it "Fibroblast of connective tissue"; CL calls it early embryonic cell (metazoa)
  • CL:0000001 (1 mention) - the report calls it "Neuron"; CL calls it primary cultured cell
  • CL:0000004 (1 mention) - the report calls it "Sensory hair cell"; CL calls it obsolete cell by organism
  • UBERON:0001756 (1 mention) - the report calls it "otic capsule"; UBERON calls it middle ear
  • UBERON:0001686 (1 mention) - the report calls it "stapes"; UBERON calls it auditory ossicle bone
  • UBERON:0001825 (1 mention) - the report calls it "cochlea"; UBERON calls it paranasal sinus
  • NCIT:C51548 (1 mention) - the report calls it "Stapedectomy"; NCIT calls it IGF1R wt Allele
  • NCIT:C51546 (1 mention) - the report calls it "Cochlear Implantation"; NCIT calls it FLT3 wt Allele
  • NCIT:C15233 (1 mention) - the report calls it "Hearing Aid"; NCIT calls it Nutrition Research, Fats, Unsaturated

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0008613 (1 mention), reported as "Otosclerosis" - HP does not contain this term
  • HP:000 (3 mentions) - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • CL:0000004 (obsolete cell by organism) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0030509 (2 mentions) - the report calls it "BMP signaling", "BMP signaling pathway"; GO calls it BMP signaling pathway
  • GO:0001837 (1 mention) - the report calls it "epithelial–mesenchymal transition in bone"; GO calls it epithelial to mesenchymal transition, and lists "epithelial-mesenchymal transition" among its other names
  • GO:0006954 (1 mention) - the report calls it "inflammatory response – tentative"; GO calls it inflammatory response

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0030509 - called "BMP signaling", "BMP signaling pathway"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.