Osteochondritis dissecans

Summary

Osteochondritis dissecans (MONDO:0017178) is a disease caused by ACAN (GenCC Definitive), with 1 cohort gene and 23 clinical trials. Top therapeutic interventions include autologous cultured chondrocytes.

At a glance

• Prevalence: 1-5 / 10 000 (Europe)
• Causal gene: ACAN (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 59
• Phenotypes (HPO): 18
• Clinical trials: 23

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	35	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0001386	Joint swelling	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0002815	Abnormality of the knee	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0001367	Abnormal joint morphology	Frequent (30-79%)
HP:0001377	Limited elbow extension	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0003088	Premature osteoarthritis	Frequent (30-79%)
HP:0003184	Decreased hip abduction	Frequent (30-79%)
HP:0006376	Limited elbow flexion	Frequent (30-79%)
HP:0010885	Avascular necrosis	Frequent (30-79%)
HP:0011843	Abnormality of skeletal physiology	Frequent (30-79%)
HP:6000917	Bone marrow edema	Frequent (30-79%)
HP:0001288	Gait disturbance	Occasional (5-29%)
HP:0002992	Abnormality of tibia morphology	Occasional (5-29%)
HP:0009050	Quadriceps muscle atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	osteochondritis dissecans
Mondo ID	MONDO:0017178
MeSH	D010008
Orphanet	2764
DOID	DOID:84
ICD-10-CM	M93.2
ICD-11	467851106
NCIT	C34878
SNOMED CT	82562007
UMLS	C0029421
MedGen	10494
GARD	0012703
MedDRA	10031231
NORD	111730
Is cancer (heuristic)	no

Also known as: familial osteochondritis dissecans · Koenig disease · Konig disease · König disease · OD · osteochondritis dissecans · osteochondritis dissecans (disease) · osteochondritis dissecans, short stature, and early-onset osteoarthritis · SSOAOD

Data availability: 59 ClinVar variants · 2 GenCC gene-disease records · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › osteonecrosis of genetic origin › osteochondritis dissecans

Related subtypes (11): Legg-Calve-Perthes disease, Thiemann disease, familial form, Scheuermann disease, Gaucher disease type I, dihydropyrimidine dehydrogenase deficiency, familial avascular necrosis of femoral head, pseudohypoparathyroidism type 1C, hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency, hereditary antithrombin deficiency, epiphysiolysis of the hip, short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

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

59 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 21 benign, 8 pathogenic, 5 likely pathogenic, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1189835	NM_001369268.1(ACAN):c.492C>A (p.Tyr164Ter)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
1199200	NM_001369268.1(ACAN):c.1552_1556del (p.Glu518fs)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
1321150	NM_001369268.1(ACAN):c.6049G>T (p.Glu2017Ter)	ACAN	Pathogenic	criteria provided, single submitter
1332835	NM_001369268.1(ACAN):c.1605-2A>C	ACAN	Pathogenic	criteria provided, single submitter
803118	NM_001369268.1(ACAN):c.2541del (p.Val848fs)	ACAN	Pathogenic	criteria provided, single submitter
997448	NM_001369268.1(ACAN):c.4844del (p.Gly1615fs)	ACAN	Pathogenic	criteria provided, single submitter
997994	NM_001369268.1(ACAN):c.1880_1883dup (p.Asp629fs)	ACAN	Pathogenic	no assertion criteria provided
997996	NM_001369268.1(ACAN):c.1861A>T (p.Lys621Ter)	ACAN	Pathogenic	no assertion criteria provided
1172552	NM_001369268.1(ACAN):c.613_616dup (p.Asp206delinsGlyTer)	ACAN	Likely pathogenic	criteria provided, single submitter
635418	NM_001369268.1(ACAN):c.-7-2A>T	ACAN	Likely pathogenic	no assertion criteria provided
976161	NM_001369268.1(ACAN):c.221dup (p.Trp75fs)	ACAN	Likely pathogenic	criteria provided, single submitter
984387	NM_001369268.1(ACAN):c.4829del (p.Pro1610fs)	ACAN	Likely pathogenic	no assertion criteria provided
998051	NM_001369268.1(ACAN):c.1120_1123del (p.Gln373_Thr374insTer)	ACAN	Likely pathogenic	no assertion criteria provided
1685260	NM_001369268.1(ACAN):c.5221G>C (p.Gly1741Arg)	ACAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446080	NM_001369268.1(ACAN):c.230G>A (p.Arg77His)	ACAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
803117	NM_001369268.1(ACAN):c.913C>T (p.Arg305Cys)	ACAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034407	NM_001369268.1(ACAN):c.1015G>A (p.Asp339Asn)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034409	NM_001369268.1(ACAN):c.6308C>T (p.Thr2103Met)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1172550	NM_001369268.1(ACAN):c.955G>A (p.Gly319Ser)	ACAN	Uncertain significance	criteria provided, single submitter
1172551	NM_001369268.1(ACAN):c.600C>G (p.Asp200Glu)	ACAN	Uncertain significance	criteria provided, single submitter
1173072	NM_001369268.1(ACAN):c.736T>G (p.Cys246Gly)	ACAN	Uncertain significance	criteria provided, single submitter
1299235	NM_001369268.1(ACAN):c.6535A>G (p.Thr2179Ala)	ACAN	Uncertain significance	criteria provided, single submitter
1328266	NM_001369268.1(ACAN):c.7389C>T (p.Gly2463=)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1449203	NM_001369268.1(ACAN):c.1447C>T (p.Arg483Cys)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
2169925	NM_001369268.1(ACAN):c.7507C>T (p.Arg2503Trp)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
252934	NM_001369268.1(ACAN):c.7358A>T (p.Asp2453Val)	ACAN	Uncertain significance	no assertion criteria provided
3466315	NM_001369268.1(ACAN):c.4745G>A (p.Gly1582Glu)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
3778944	NM_001369268.1(ACAN):c.2522C>T (p.Pro841Leu)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
3778946	NM_001369268.1(ACAN):c.324C>A (p.Asn108Lys)	ACAN	Uncertain significance	criteria provided, single submitter
3778951	NM_001369268.1(ACAN):c.5015C>G (p.Ala1672Gly)	ACAN	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 4 · 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
ACAN	Definitive	Autosomal dominant	short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACAN	Orphanet:171866	Spondyloepimetaphyseal dysplasia, aggrecan type
ACAN	Orphanet:251262	Familial osteochondritis dissecans
ACAN	Orphanet:435804	Short stature-advanced bone age-early-onset osteoarthritis syndrome
ACAN	Orphanet:93283	Spondyloepiphyseal dysplasia, Kimberley type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACAN	HGNC:319	ENSG00000157766	P16112	Aggrecan core protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACAN	Aggrecan core protein	This proteoglycan is a major component of extracellular matrix of cartilagenous tissues.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Complement	1	268.0×	0.004

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACAN	Complement	yes		Sushi_SCR_CCP_dom, Link_dom, EGF

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
descending thoracic aorta	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACAN	181	broad	marker	tibia, cartilage tissue, descending thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACAN	2,200

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACAN	P16112	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CHST6 causes MCDC1	1	1427.5×	0.002	ACAN
Defective ST3GAL3 causes MCT12 and EIEE15	1	1427.5×	0.002	ACAN
Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)	1	1427.5×	0.002	ACAN
Keratan sulfate degradation	1	713.8×	0.002	ACAN
Keratan sulfate biosynthesis	1	380.7×	0.004	ACAN
ECM proteoglycans	1	150.3×	0.008	ACAN
Degradation of the extracellular matrix	1	117.7×	0.008	ACAN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal system development	1	125.8×	0.017	ACAN
central nervous system development	1	115.4×	0.017	ACAN
cell adhesion	1	37.5×	0.029	ACAN
proteolysis	1	34.2×	0.029	ACAN

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
ACAN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	ACAN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACAN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 23.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	17
PHASE3	3
PHASE4	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01283737	PHASE4	WITHDRAWN	Use of Demineralised Bone Matrix (DBX) in Osteochondritis Dissecans (OCD)
NCT03588975	PHASE3	RECRUITING	A Study of MACI in Patients Aged 10 to 17 Years With Symptomatic Chondral or Osteochondral Defects of the Knee
NCT01498029	PHASE3	UNKNOWN	Knee Articular Cartilage Repair: Cartilage Autograft Implantation System Versus Conventional Microfracture
NCT02993510	PHASE3	COMPLETED	A Randomized Controlled Trial Comparing Chondro-Gide® to Microfracture Alone for Treatment of Knee Cartilage Defects.
NCT01694823	PHASE1/PHASE2	UNKNOWN	Safety and Efficacy Study of Cells Sheet-Autologous Chondrocyte Implantation to Treat Articular Cartilage Defects
NCT01159899	EARLY_PHASE1	UNKNOWN	Transplantation of Bone Marrow Stem Cells Stimulated by Proteins Scaffold to Heal Defects Articular Cartilage of the Knee
NCT01458782	Not specified	ACTIVE_NOT_RECRUITING	ACI-C Versus AMIC. A Randomized Trial Comparing Two Methods for Repair of Cartilage Defects in the Knee
NCT02664337	Not specified	ENROLLING_BY_INVITATION	Conjoint Analysis of Patient Preferences in Joint Interventions
NCT02771496	Not specified	RECRUITING	Osteochondritis Dissecans of Knee Prospective Cohort
NCT04364334	Not specified	RECRUITING	Knee Registry (Knieregister)
NCT06462040	Not specified	RECRUITING	Evaluation of Clinical and Radiological Outcomes in Patients Undergoing Fixation of Osteochondral Fragments With Reasorbable Screws in the Knee Joint
NCT07332182	Not specified	NOT_YET_RECRUITING	MaioRegen Prime Study for the Treatment of Deep Osteochondral Lesion of the Knee
NCT07439107	Not specified	ACTIVE_NOT_RECRUITING	Treatment Outcomes for Osteochondritis Dissecans of the Knee: A Cohort Study
NCT00881023	Not specified	TERMINATED	Cartilage Autograft Implantation System (CAIS) for the Repair of Knee Cartilage Through Cartilage Regeneration
NCT01329445	Not specified	UNKNOWN	DeNovo NT Longitudinal Data Collection (LDC) Knee Study
NCT01347892	Not specified	UNKNOWN	DeNovo NT Ankle LDC Study
NCT01409447	Not specified	UNKNOWN	Repair of Articular Osteochondral Defect
NCT01455987	Not specified	UNKNOWN	Osteochondritis Dissecans of the Knee
NCT01471236	Not specified	COMPLETED	Evaluation of the Agili-C Biphasic Implant in the Knee Joint
NCT02397278	Not specified	COMPLETED	Intra Articular Injections With Platelet Rich Plasma in Patients With Juvenile Osteochondritis Dissecans of the Knee
NCT03452098	Not specified	COMPLETED	Post-Operative Rehabilitation of Knee Osteochondral Defect: A Case Series
NCT03656185	Not specified	UNKNOWN	Elbow Arthroscopy Data Analysis
NCT04297449	Not specified	COMPLETED	Prospective 2-year Data Collection of the First 10 Patients After Ankle Spacer Implantation

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AUTOLOGOUS CULTURED CHONDROCYTES	4	1