Otospondylomegaepiphyseal dysplasia

Summary

Otospondylomegaepiphyseal dysplasia (MONDO:0008975) is a disease caused by COL11A2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COL11A2 (GenCC Definitive)
• Cohort genes: 2
• Phenotypes (HPO): 43

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0001367	Abnormal joint morphology	Very frequent (80-99%)
HP:0003468	Abnormal vertebral morphology	Very frequent (80-99%)
HP:0003498	Disproportionate short stature	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0040163	Abnormal pelvis bone morphology	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000193	Bifid uvula	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0001156	Brachydactyly	Frequent (30-79%)
HP:0002656	Epiphyseal dysplasia	Frequent (30-79%)
HP:0006375	Dumbbell-shaped femur	Frequent (30-79%)
HP:0009826	Limb undergrowth	Frequent (30-79%)
HP:0011314	Abnormality of long bone morphology	Frequent (30-79%)
HP:0011867	Abnormality of the wing of the ilium	Frequent (30-79%)
HP:0012368	Flat face	Frequent (30-79%)
HP:0000162	Glossoptosis	Occasional (5-29%)
HP:0000358	Posteriorly rotated ears	Occasional (5-29%)
HP:0000470	Short neck	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000926	Platyspondyly	Occasional (5-29%)
HP:0001376	Limitation of joint mobility	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0001852	Sandal gap	Occasional (5-29%)
HP:0002758	Osteoarthritis	Occasional (5-29%)
HP:0002834	Flared femoral metaphysis	Occasional (5-29%)
HP:0002938	Lumbar hyperlordosis	Occasional (5-29%)
HP:0002982	Tibial bowing	Occasional (5-29%)
HP:0003037	Enlarged joints	Occasional (5-29%)
HP:0003417	Coronal cleft vertebrae	Occasional (5-29%)
HP:0009803	Short phalanx of finger	Occasional (5-29%)
HP:0010049	Short metacarpal	Occasional (5-29%)
HP:0010502	Fibular bowing	Occasional (5-29%)
HP:0100569	Abnormally ossified vertebrae	Occasional (5-29%)
HP:0000518	Cataract	Excluded (0%)
HP:0000541	Retinal detachment	Excluded (0%)
HP:0007964	Degenerative vitreoretinopathy	Excluded (0%)
HP:0011003	High myopia	Excluded (0%)
HP:0000486	Strabismus	Very rare (<1-4%)
HP:0000540	Hypermetropia	Very rare (<1-4%)
HP:0025573	Mild myopia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	otospondylomegaepiphyseal dysplasia
Mondo ID	MONDO:0008975
OMIM	184840
Orphanet	1427
DOID	DOID:0080026
ICD-11	1885284987
SNOMED CT	254060000
UMLS	C4520892
MedGen	1617409
GARD	0004130
Is cancer (heuristic)	no

Also known as: Insley-Astley syndrome · Nance Sweeney chondrodysplasia · OSMED · OSMED syndrome · oto-spondylo-mega-epiphyseal dysplasia · otospondylmegaepiphyseal dysplasia · otospondylomegaepiphyseal dysplasia

Data availability: 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › spondyloepiphyseal dysplasia › otospondylomegaepiphyseal dysplasia

Related subtypes (43): hip dysplasia, Beukes type, spondyloepiphyseal dysplasia with congenital joint dislocations, Marshall syndrome, metatropic dysplasia, spondyloepiphyseal dysplasia with punctate corneal dystrophy, spondyloepiphyseal dysplasia, MacDermot type, progressive pseudorheumatoid arthropathy of childhood, Dyggve-Melchior-Clausen disease, dyssegmental dysplasia, Rolland-Desbuquois type, Silverman-Handmaker type dyssegmental dysplasia, Wolcott-Rallison syndrome, Schimke immuno-osseous dysplasia, Richieri Costa-da Silva syndrome, Schwartz-Jampel syndrome, X-linked spondyloepimetaphyseal dysplasia, CODAS syndrome, spondyloepiphyseal dysplasia, Reardon type, brachyolmia-amelogenesis imperfecta syndrome, spondyloepiphyseal dysplasia with coronal craniosynostosis, cataracts, cleft palate, and intellectual disability, anauxetic dysplasia, spondyloepiphyseal dysplasia, Kimberley type, spondyloepiphyseal dysplasia, Cantu type, Ehlers-Danlos syndrome, spondylocheirodysplastic type, spondylo-megaepiphyseal-metaphyseal dysplasia, brachydactylous dwarfism, Mseleni type, TMEM165-congenital disorder of glycosylation, Steel syndrome, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Roifman syndrome, progressive spondyloepimetaphyseal dysplasia-short stature-short fourth metatarsals-intellectual disability syndrome, even-plus syndrome, Smith-McCort dysplasia, cono-spondylar dysplasia, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, Stickler syndrome, spondyloepiphyseal dysplasia tarda, spondyloepiphyseal dysplasia, kondo-fu type, spondyloepiphyseal dysplasia, nishimura type, immunoskeletal dysplasia with neurodevelopmental abnormalities, COL2A1-related spondyloepiphyseal dysplasia, MIR140-related spondyloepiphyseal dysplasia, MGP-related spondyloepiphyseal dysplasia, spondyloepiphyseal dysplasia, Holling type

Subtypes (2): otospondylomegaepiphyseal dysplasia, autosomal dominant, otospondylomegaepiphyseal dysplasia, autosomal recessive

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 66 · Orphanet: 23 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
COL11A2	Definitive	Autosomal dominant	otospondylomegaepiphyseal dysplasia	20
COL2A1	Definitive	Autosomal dominant	spondyloepiphyseal dysplasia with metatarsal shortening	46

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL11A2	Orphanet:1427	Autosomal recessive otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:2021	Fibrochondrogenesis
COL11A2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COL11A2	HGNC:2187	ENSG00000204248	P13942	Collagen alpha-2(XI) chain	gencc
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL11A2	Collagen alpha-2(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL11A2	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1
cartilage tissue	1
corpus epididymis	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL11A2	134	broad	yes	pituitary gland, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL2A1	2,491
COL11A2	1,583

Intra-cohort edges

A	B	Sources
COL11A2	COL2A1	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL2A1	P02458	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL11A2	P13942	50.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET activates PTK2 signaling	2	380.7×	7e-05	COL11A2, COL2A1
Collagen chain trimerization	2	259.6×	7e-05	COL11A2, COL2A1
Developmental Lineage of Pancreatic Ductal Cells	2	228.4×	7e-05	COL11A2, COL2A1
Assembly of collagen fibrils and other multimeric structures	2	200.3×	7e-05	COL11A2, COL2A1
Collagen degradation	2	175.7×	7e-05	COL11A2, COL2A1
Collagen biosynthesis and modifying enzymes	2	170.4×	7e-05	COL11A2, COL2A1
Non-integrin membrane-ECM interactions	2	154.3×	8e-05	COL11A2, COL2A1
Fibronectin matrix formation	1	285.5×	0.006	COL2A1
Signaling by PDGF	1	126.9×	0.010	COL2A1
NCAM1 interactions	1	124.1×	0.010	COL2A1
ECM proteoglycans	1	75.1×	0.016	COL2A1
Integrin cell surface interactions	1	67.2×	0.016	COL2A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	43.6×	0.023	COL2A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cartilage development	2	251.5×	2e-04	COL11A2, COL2A1
roof of mouth development	2	247.8×	2e-04	COL11A2, COL2A1
collagen fibril organization	2	224.7×	2e-04	COL11A2, COL2A1
skeletal system development	2	125.8×	4e-04	COL11A2, COL2A1
sensory perception of sound	2	100.9×	5e-04	COL11A2, COL2A1
soft palate development	1	1685.2×	0.002	COL11A2
otic vesicle development	1	1404.3×	0.002	COL2A1
anterior head development	1	1404.3×	0.002	COL2A1
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.002	COL2A1
proteoglycan metabolic process	1	936.2×	0.003	COL2A1
notochord development	1	842.6×	0.003	COL2A1
limb bud formation	1	766.0×	0.003	COL2A1
embryonic skeletal joint morphogenesis	1	766.0×	0.003	COL2A1
cartilage condensation	1	383.0×	0.005	COL2A1
tissue homeostasis	1	280.9×	0.005	COL2A1
cellular response to BMP stimulus	1	280.9×	0.005	COL2A1
endochondral ossification	1	271.8×	0.005	COL2A1
extrinsic apoptotic signaling pathway in absence of ligand	1	234.1×	0.006	COL2A1
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	205.5×	0.006	COL2A1
heart morphogenesis	1	187.2×	0.007	COL2A1
chondrocyte differentiation	1	150.5×	0.008	COL2A1
inner ear morphogenesis	1	150.5×	0.008	COL2A1
central nervous system development	1	57.7×	0.019	COL2A1
regulation of gene expression	1	41.7×	0.025	COL2A1
visual perception	1	39.8×	0.025	COL2A1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL11A2	0	0
COL2A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
COL2A1	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	COL11A2, COL2A1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
COL11A2	0	—
COL2A1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.