Hereditary multiple osteochondromas

Summary

Hereditary multiple osteochondromas (MONDO:0005508) is a disease with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 1,016
• Phenotypes (HPO): 56
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3	Europe	Validated
Point prevalence	>1 / 1000	100	Specific population	Validated
Point prevalence	1-9 / 1 000 000	0.9	United Kingdom	Validated
Point prevalence	1-9 / 100 000	1.35	Netherlands	Validated
Point prevalence	1-9 / 100 000	2	United States	Validated

Signs & symptoms

Clinical features (HPO)

56 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0030431	Osteochondroma	Obligate (100%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0002763	Abnormal cartilage morphology	Frequent (30-79%)
HP:0002815	Abnormality of the knee	Frequent (30-79%)
HP:0002823	Abnormality of femur morphology	Frequent (30-79%)
HP:0003330	Abnormal bone structure	Frequent (30-79%)
HP:0003959	Deformed forearm bones	Frequent (30-79%)
HP:0004302	Functional motor deficit	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0012531	Pain	Frequent (30-79%)
HP:0040069	Abnormal lower limb bone morphology	Frequent (30-79%)
HP:0001369	Arthritis	Occasional (5-29%)
HP:0002673	Coxa valga	Occasional (5-29%)
HP:0002857	Genu valgum	Occasional (5-29%)
HP:0002991	Abnormal fibula morphology	Occasional (5-29%)
HP:0002992	Abnormality of tibia morphology	Occasional (5-29%)
HP:0003016	Metaphyseal widening	Occasional (5-29%)
HP:0003026	Short long bone	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)
HP:0003977	Deformed radius	Occasional (5-29%)
HP:0005922	Abnormal hand morphology	Occasional (5-29%)
HP:0006385	Short lower limbs	Occasional (5-29%)
HP:0006487	Bowing of the long bones	Occasional (5-29%)
HP:0008800	Limited hip movement	Occasional (5-29%)
HP:0009821	Forearm undergrowth	Occasional (5-29%)
HP:0009826	Limb undergrowth	Occasional (5-29%)
HP:0010049	Short metacarpal	Occasional (5-29%)
HP:0010501	Limitation of knee mobility	Occasional (5-29%)
HP:0025232	Bursitis	Occasional (5-29%)
HP:0030883	Femoroacetabular impingement	Occasional (5-29%)
HP:0032510	Tendon pain	Occasional (5-29%)
HP:0040071	Abnormal morphology of ulna	Occasional (5-29%)
HP:0100555	Asymmetric growth	Occasional (5-29%)
HP:0100559	Lower limb asymmetry	Occasional (5-29%)
HP:0000016	Urinary retention	Very rare (<1-4%)
HP:0000896	Rib exostoses	Very rare (<1-4%)
HP:0000918	Scapular exostoses	Very rare (<1-4%)
HP:0001191	Abnormal carpal morphology	Very rare (<1-4%)
HP:0001850	Abnormality of the tarsal bones	Very rare (<1-4%)
HP:0002015	Dysphagia	Very rare (<1-4%)
HP:0002107	Pneumothorax	Very rare (<1-4%)
HP:0002144	Tethered cord	Very rare (<1-4%)
HP:0002176	Spinal cord compression	Very rare (<1-4%)
HP:0002318	Cervical myelopathy	Very rare (<1-4%)
HP:0003396	Syringomyelia	Very rare (<1-4%)
HP:0003406	Peripheral nerve compression	Very rare (<1-4%)
HP:0004684	Talipes valgus	Very rare (<1-4%)
HP:0005214	Intestinal obstruction	Very rare (<1-4%)
HP:0006765	Chondrosarcoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary multiple osteochondromas
Mondo ID	MONDO:0005508
MeSH	D005097
OMIM	133700
Orphanet	321
DOID	DOID:206
ICD-11	146330302, 1578364807
NCIT	C5183
SNOMED CT	254044004, 716742001
UMLS	C0015306
MedGen	4612
GARD	0007035
NORD	1233
Is cancer (heuristic)	no

Also known as: Bessel-Hagen disease · exostoses, multiple · EXT · hereditary multiple exostoses · hereditary multiple exostoses 1 · hereditary multiple exostoses 2 · hereditary multiple exostoses 3 · hereditary multiple exostosis · HMO · multiple cartilaginous exostoses · multiple exostoses · osteochondromatosis syndrome · osteochondromatosis syndrome (disorder) [ambiguous]

Data availability: 1,016 ClinVar variants · 2 GenCC gene-disease records · 5 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone remodeling disease › hyperostosis › exostosis › hereditary multiple osteochondromas

Related subtypes (2): heel spur, Heberden’s node

Subtypes (3): exostoses, multiple, type 1, exostoses, multiple, type 2, exostoses, multiple, type III

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

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

217 uncertain significance, 175 pathogenic, 139 likely benign, 24 conflicting classifications of pathogenicity, 19 benign, 12 likely pathogenic, 9 pathogenic/likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3245402	NC_000008.10:g.(?118649470)(122282519_?)del	CCN3	Pathogenic	criteria provided, single submitter
1050990	NM_000127.3(EXT1):c.995_1000del (p.Thr332_Cys334delinsSer)	EXT1	Pathogenic	criteria provided, single submitter
1066566	NM_000127.3(EXT1):c.1015G>A (p.Gly339Ser)	EXT1	Pathogenic	criteria provided, single submitter
1068505	NM_000127.3(EXT1):c.557_558del (p.Asn186fs)	EXT1	Pathogenic	criteria provided, single submitter
1068706	NM_000127.3(EXT1):c.1845del (p.Tyr616fs)	EXT1	Pathogenic	criteria provided, single submitter
1068794	NM_000127.3(EXT1):c.540_962+399del	EXT1	Pathogenic	criteria provided, single submitter
1068987	NM_000127.3(EXT1):c.1522del (p.Gln508fs)	EXT1	Pathogenic	criteria provided, single submitter
1069069	NM_000127.3(EXT1):c.1126del (p.Gln376fs)	EXT1	Pathogenic	criteria provided, single submitter
1069234	NM_000127.3(EXT1):c.1882A>T (p.Lys628Ter)	EXT1	Pathogenic	criteria provided, single submitter
1069287	NM_000127.3(EXT1):c.487_488insAA (p.Arg163fs)	EXT1	Pathogenic	criteria provided, single submitter
1069505	NM_000127.3(EXT1):c.1723-2A>C	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069692	NM_000127.3(EXT1):c.1998dup (p.Leu667fs)	EXT1	Pathogenic	criteria provided, single submitter
1069912	NM_000127.3(EXT1):c.1285-1G>T	EXT1	Pathogenic	criteria provided, single submitter
1070211	NM_000127.3(EXT1):c.60_64del (p.Tyr22fs)	EXT1	Pathogenic	criteria provided, single submitter
1071748	NM_000127.3(EXT1):c.1064G>A (p.Cys355Tyr)	EXT1	Pathogenic	criteria provided, single submitter
1071749	NM_000127.3(EXT1):c.1027G>A (p.Gly343Arg)	EXT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071829	NM_000127.3(EXT1):c.287_290dup (p.Cys98fs)	EXT1	Pathogenic	criteria provided, single submitter
1072962	NC_000008.10:g.(?118819436)(118847810_?)del	EXT1	Pathogenic	criteria provided, single submitter
1072963	NC_000008.10:g.(?118811951)(118834836_?)del	EXT1	Pathogenic	criteria provided, single submitter
1073473	NM_000127.3(EXT1):c.1157T>G (p.Leu386Ter)	EXT1	Pathogenic	criteria provided, single submitter
1073635	NM_000127.3(EXT1):c.393C>A (p.Tyr131Ter)	EXT1	Pathogenic	criteria provided, single submitter
1074978	NM_000127.3(EXT1):c.711_712del (p.Phe237_Ser238insTer)	EXT1	Pathogenic	criteria provided, single submitter
1075400	NM_000127.3(EXT1):c.1906del (p.His636fs)	EXT1	Pathogenic	criteria provided, single submitter
1075642	NM_000127.3(EXT1):c.752del (p.Phe250_Leu251insTer)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076030	NM_000127.3(EXT1):c.203G>A (p.Trp68Ter)	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1076975	NC_000008.10:g.(?118842449)(118842608_?)del	EXT1	Pathogenic	criteria provided, single submitter
1076976	NC_000008.10:g.(?_118825208)_119035925del	EXT1	Pathogenic	criteria provided, single submitter
1208138	NM_000127.3(EXT1):c.1536+1G>A	EXT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324356	NM_000127.3(EXT1):c.1421T>G (p.Leu474Ter)	EXT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1329470	NM_000127.3(EXT1):c.1290_1297del (p.Ile430fs)	EXT1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 6 · 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
EXT1	Definitive	Autosomal dominant	exostoses, multiple, type 1	6
EXT2	Definitive	Autosomal dominant	exostoses, multiple, type 2	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EXT1	Orphanet:321	Multiple osteochondromas
EXT1	Orphanet:502	Trichorhinophalangeal syndrome type 2
EXT1	Orphanet:55880	Chondrosarcoma
EXT2	Orphanet:321	Multiple osteochondromas
EXT2	Orphanet:466926	Seizures-scoliosis-macrocephaly syndrome
EXT2	Orphanet:52022	Potocki-Shaffer syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EXT1	HGNC:3512	ENSG00000182197	Q16394	Exostosin-1	gencc,clinvar
EXT2	HGNC:3513	ENSG00000151348	Q93063	Exostosin-2	gencc,clinvar
AARD	HGNC:33842	ENSG00000205002	Q4LEZ3	Alanine- and arginine-rich domain-containing protein	clinvar
CCN3	HGNC:7885	ENSG00000136999	P48745	CCN family member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EXT1	Exostosin-1	Glycosyltransferase forming with EXT2 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone.
EXT2	Exostosin-2	Glycosyltransferase forming with EXT1 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone.
CCN3	CCN family member 3	Immediate-early protein playing a role in various cellular processes including proliferation, adhesion, migration, differentiation and survival.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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
Enzyme (other)	2	6.0×	0.074
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EXT1	Enzyme (other)	yes	2.4.1.224	Exostosin, GT64_dom, Nucleotide-diphossugar_trans
EXT2	Enzyme (other)	yes	2.4.1.224	Exostosin, GT64_dom, Nucleotide-diphossugar_trans
AARD	Other/Unknown	no		FAM167_domain
CCN3	Other/Unknown	no		IGFBP-like, TSP1_rpt, VWF_dom

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	2
descending thoracic aorta	1
saphenous vein	1
cartilage tissue	1
smooth muscle tissue	1
left testis	1
right testis	1
testis	1
adrenal cortex	1
blood vessel layer	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EXT1	285	ubiquitous	marker	stromal cell of endometrium, saphenous vein, descending thoracic aorta
EXT2	269	ubiquitous	marker	stromal cell of endometrium, cartilage tissue, smooth muscle tissue
AARD	116	broad	marker	left testis, testis, right testis
CCN3	237	ubiquitous	marker	right coronary artery, blood vessel layer, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EXT1	1,449
EXT2	1,242
CCN3	768
AARD	279

Intra-cohort edges

A	B	Sources
EXT1	EXT2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EXT1	Q16394	6
EXT2	Q93063	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AARD	Q4LEZ3	78.24
CCN3	P48745	77.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 4 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
Defective EXT2 causes exostoses 2	2	815.7×	2e-06	EXT1, EXT2
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	2	815.7×	2e-06	EXT1, EXT2
HS-GAG biosynthesis	2	346.1×	8e-06	EXT1, EXT2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fluid transport	2	2808.7×	1e-05	EXT1, EXT2
polysaccharide biosynthetic process	2	1203.7×	5e-05	EXT1, EXT2
heparin proteoglycan biosynthetic process	2	842.6×	5e-05	EXT1, EXT2
multicellular organismal-level water homeostasis	2	842.6×	5e-05	EXT1, EXT2
sulfation	2	526.6×	1e-04	EXT1, EXT2
sodium ion homeostasis	2	468.1×	1e-04	EXT1, EXT2
glycosaminoglycan biosynthetic process	2	421.3×	1e-04	EXT1, EXT2
heart contraction	2	383.0×	1e-04	EXT1, EXT2
cell adhesion mediated by integrin	2	337.0×	2e-04	EXT1, CCN3
heparan sulfate proteoglycan biosynthetic process	2	280.9×	2e-04	EXT1, EXT2
hematopoietic stem cell homeostasis	2	280.9×	2e-04	EXT1, CCN3
vasodilation	2	183.2×	4e-04	EXT1, EXT2
chondrocyte differentiation	2	150.5×	5e-04	EXT2, CCN3
ossification	2	113.9×	9e-04	EXT1, EXT2
regulation of blood pressure	2	110.9×	9e-04	EXT1, EXT2
hypersensitivity	1	4213.0×	0.001	EXT1
heart field specification	1	4213.0×	0.001	EXT1
lymphocyte adhesion to endothelial cell of high endothelial venule	1	4213.0×	0.001	EXT1
smoothened signaling pathway involved in lung development	1	4213.0×	0.001	EXT1
sweat gland development	1	4213.0×	0.001	EXT1
perichondral bone morphogenesis	1	4213.0×	0.001	EXT1
smooth muscle cell proliferation	1	2106.5×	0.002	CCN3
stomach development	1	2106.5×	0.002	EXT1
mesenchymal cell differentiation involved in bone development	1	2106.5×	0.002	EXT1
response to leukemia inhibitory factor	1	2106.5×	0.002	EXT1
developmental growth involved in morphogenesis	1	1404.3×	0.003	EXT1
response to heparin	1	1404.3×	0.003	EXT1
embryonic skeletal limb joint morphogenesis	1	1053.2×	0.003	EXT1
chondroitin sulfate proteoglycan metabolic process	1	1053.2×	0.003	EXT1
endochondral bone morphogenesis	1	1053.2×	0.003	EXT2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EXT1	0	0
EXT2	0	0
AARD	0	0
CCN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EXT1	2.4.1.224, 2.4.1.225	glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase
EXT2	2.4.1.224, 2.4.1.225	glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	2	EXT1, EXT2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	AARD, CCN3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EXT1	0	—
EXT2	0	—
AARD	0	—
CCN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06703736	Not specified	RECRUITING	Functional and Morphological Characterization of Multiple Osteochondromas Disorder