Legg-Calve-Perthes disease

Summary

Legg-Calve-Perthes disease (MONDO:0007885) is a disease caused by COL2A1 (GenCC Strong), with 2 cohort genes and 12 clinical trials. Top therapeutic interventions include triamcinolone hexacetonide.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: COL2A1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 59
• Phenotypes (HPO): 8
• Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0001373	Joint dislocation	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0010885	Avascular necrosis	Very frequent (80-99%)
HP:0100773	Cartilage destruction	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Legg-Calve-Perthes disease
Mondo ID	MONDO:0007885
MeSH	D007873
OMIM	150600
Orphanet	2380
DOID	DOID:14415
NCIT	C34766
SNOMED CT	15739006
UMLS	C1442965
MedGen	730669
GARD	0006874
MedDRA	10034735
NORD	1353
Is cancer (heuristic)	no

Also known as: aseptic necrosis of the capital femoral epiphysis · LCPD · Legg Calvé Perthes Disease · Legg-CALVE-Perthes disease · Legg-Calve-Perthes disease · Legg-Calve-Perthes symptom · Legg-Calve-Perthes syndrome · Legg-Calvé-Perthes disease · Legg-Perthes disease · osteochondritis deformans · osteochondritis of the capital femoral epiphysis · Osteochondrosis of the capital femoral epiphysis · Perthe’s disease · Perthes disease

Data availability: 59 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › osteonecrosis › osteochondrosis › Legg-Calve-Perthes disease

Related subtypes (10): Osgood-Schlatter disease, Thiemann disease, familial form, Scheuermann disease, dihydropyrimidine dehydrogenase deficiency, osteochondritis of tarsal/metatarsal bone, medial condensing osteitis of the clavicle, Kienbock disease, panner disease, Sinding-Larsen-Johansson disease, Freiberg disease

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:

14 conflicting classifications of pathogenicity, 10 likely pathogenic, 9 pathogenic, 9 benign/likely benign, 6 uncertain significance, 6 pathogenic/likely pathogenic, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
267809	46;XY;t(8;9)(q13;p22)dn		Pathogenic	criteria provided, single submitter
1074468	NM_001844.5(COL2A1):c.1A>G (p.Met1Val)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1224342	NM_001844.5(COL2A1):c.3121G>A (p.Gly1041Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1455692	NM_001844.5(COL2A1):c.2858del (p.Pro953fs)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17366	NM_001844.5(COL2A1):c.2965C>T (p.Arg989Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17383	NM_001844.5(COL2A1):c.1693C>T (p.Arg565Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17393	NM_001844.5(COL2A1):c.3508G>A (p.Gly1170Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
17395	NM_001844.5(COL2A1):c.1957C>T (p.Arg653Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
195148	NM_001844.5(COL2A1):c.258C>A (p.Cys86Ter)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
195742	NM_001844.5(COL2A1):c.1510G>A (p.Gly504Ser)	COL2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2859637	NM_001844.5(COL2A1):c.3085G>T (p.Gly1029Cys)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382798	NM_001844.5(COL2A1):c.3040G>A (p.Gly1014Arg)	COL2A1	Pathogenic	criteria provided, single submitter
449001	NM_001844.5(COL2A1):c.905C>T (p.Ala302Val)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988569	NM_001844.5(COL2A1):c.2059G>A (p.Gly687Ser)	COL2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39035	NM_024312.5(GNPTAB):c.1514G>A (p.Cys505Tyr)	GNPTAB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1013347	NM_001844.5(COL2A1):c.1888G>A (p.Gly630Ser)	COL2A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1516689	NM_001844.5(COL2A1):c.1618G>A (p.Gly540Ser)	COL2A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382056	NM_001844.5(COL2A1):c.2771G>A (p.Gly924Glu)	COL2A1	Likely pathogenic	criteria provided, single submitter
3382294	NM_001844.5(COL2A1):c.3293G>A (p.Gly1098Glu)	COL2A1	Likely pathogenic	criteria provided, single submitter
3382404	NM_001844.5(COL2A1):c.3679_3680insAA (p.Gly1227fs)	COL2A1	Likely pathogenic	criteria provided, single submitter
3574632	NM_001844.5(COL2A1):c.1529G>T (p.Gly510Val)	COL2A1	Likely pathogenic	criteria provided, single submitter
3574633	NM_001844.5(COL2A1):c.1365+3A>C	COL2A1	Likely pathogenic	criteria provided, single submitter
3574634	NM_001844.5(COL2A1):c.917_918delinsA (p.Gly306fs)	COL2A1	Likely pathogenic	criteria provided, single submitter
4796517	NM_001844.5(COL2A1):c.2464-2A>T	COL2A1	Likely pathogenic	criteria provided, single submitter
4796588	NM_001844.5(COL2A1):c.2957C>T (p.Pro986Leu)	COL2A1	Likely pathogenic	criteria provided, single submitter
1003871	NM_001844.5(COL2A1):c.1057G>A (p.Ala353Thr)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1011511	NM_001844.5(COL2A1):c.2947G>A (p.Val983Ile)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1019069	NM_001844.5(COL2A1):c.4348A>G (p.Ile1450Val)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020209	NM_001844.5(COL2A1):c.3007G>A (p.Glu1003Lys)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1386179	NM_001844.5(COL2A1):c.1757G>A (p.Arg586His)	COL2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 46 · Orphanet: 20 · 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
COL2A1	Strong	Autosomal dominant	Legg-Calve-Perthes disease	46

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
GNPTAB	Orphanet:423461	Mucolipidosis type III alpha/beta
GNPTAB	Orphanet:576	Mucolipidosis type II

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
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	gencc,clinvar
GNPTAB	HGNC:29670	ENSG00000111670	Q3T906	N-acetylglucosamine-1-phosphotransferase subunits alpha/beta	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.
GNPTAB	N-acetylglucosamine-1-phosphotransferase subunits alpha/beta	Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
GNPTAB	Enzyme (other)	yes	2.7.8.17	Notch_dom, EF_hand_dom, DMAP1-bd

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tibia	2
cartilage tissue	1
corpus epididymis	1
endothelial cell	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis
GNPTAB	290	ubiquitous	marker	tibia, endothelial cell, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL2A1	2,491
GNPTAB	1,518

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
COL2A1	P02458	11
GNPTAB	Q3T906	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 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
Fibronectin matrix formation	1	571.0×	0.008	COL2A1
MET activates PTK2 signaling	1	380.7×	0.008	COL2A1
Collagen chain trimerization	1	259.6×	0.008	COL2A1
Signaling by PDGF	1	253.8×	0.008	COL2A1
NCAM1 interactions	1	248.3×	0.008	COL2A1
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.008	COL2A1
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.008	COL2A1
Collagen degradation	1	175.7×	0.008	COL2A1
Collagen biosynthesis and modifying enzymes	1	170.4×	0.008	COL2A1
Non-integrin membrane-ECM interactions	1	154.3×	0.008	COL2A1
ECM proteoglycans	1	150.3×	0.008	COL2A1
Integrin cell surface interactions	1	134.3×	0.008	COL2A1
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	1	87.2×	0.011	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
N-glycan processing to lysosome	1	4213.0×	0.004	GNPTAB
secretion of lysosomal enzymes	1	1685.2×	0.004	GNPTAB
otic vesicle development	1	1404.3×	0.004	COL2A1
anterior head development	1	1404.3×	0.004	COL2A1
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.004	COL2A1
carbohydrate phosphorylation	1	1053.2×	0.004	GNPTAB
proteoglycan metabolic process	1	936.2×	0.004	COL2A1
notochord development	1	842.6×	0.004	COL2A1
limb bud formation	1	766.0×	0.004	COL2A1
embryonic skeletal joint morphogenesis	1	766.0×	0.004	COL2A1
cartilage condensation	1	383.0×	0.007	COL2A1
tissue homeostasis	1	280.9×	0.007	COL2A1
cellular response to BMP stimulus	1	280.9×	0.007	COL2A1
endochondral ossification	1	271.8×	0.007	COL2A1
extrinsic apoptotic signaling pathway in absence of ligand	1	234.1×	0.008	COL2A1
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	205.5×	0.009	COL2A1
heart morphogenesis	1	187.2×	0.009	COL2A1
lysosome organization	1	153.2×	0.009	GNPTAB
chondrocyte differentiation	1	150.5×	0.009	COL2A1
inner ear morphogenesis	1	150.5×	0.009	COL2A1
cartilage development	1	125.8×	0.010	COL2A1
roof of mouth development	1	123.9×	0.010	COL2A1
collagen fibril organization	1	112.3×	0.011	COL2A1
skeletal system development	1	62.9×	0.018	COL2A1
central nervous system development	1	57.7×	0.019	COL2A1
sensory perception of sound	1	50.5×	0.021	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: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COL2A1	0	0
GNPTAB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
COL2A1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GNPTAB	2.7.8.17	UDP-N-acetylglucosamine-lysosomal-enzyme N-acetylglucosaminephosphotransferase

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	1	GNPTAB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	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)
COL2A1	2	—
GNPTAB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00208468	PHASE3	TERMINATED	A Randomised Multi-centre Study to Compare the Long-term Performance of the Future Hip to 3 Other Implants in Primary Total Hip Replacement
NCT02040714	Not specified	ENROLLING_BY_INVITATION	Multicenter Prospective Cohort Study on Current Treatments of Legg-Calvé-Perthes Disease
NCT03885960	Not specified	ACTIVE_NOT_RECRUITING	Perthes Disease in Norway
NCT05734651	Not specified	RECRUITING	PROMIS Evaluation Study
NCT06823089	Not specified	RECRUITING	Early Feasibility Study of Cartilage Defect Repair
NCT07122323	Not specified	ENROLLING_BY_INVITATION	Robotic Arm-assisted THA Vs. Conventional THA in Legg-Calvé-Perthes Disease
NCT01026909	Not specified	TERMINATED	Intraarticular Corticosteroid Therapy in Perthes Disease.
NCT02087436	Not specified	COMPLETED	Taperloc Complete Microplasty vs Taperloc Complete Standard: Randomized Controlled Study on Bone Mineral Density
NCT02087449	Not specified	TERMINATED	Evaluate E1 Wear, Clinical Performance of E1 Liner in THA in Korean Patient Population
NCT02676271	Not specified	COMPLETED	The Long Term Outcome of Varus Derotational Osteotomy for Legg-Calvé-Perthes’ Disease
NCT02795494	Not specified	UNKNOWN	WOMAC Hip Score in Children and Adolescents With Perthes Disease
NCT05840146	Not specified	COMPLETED	Kineesiotaping for Patients With LCPD

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRIAMCINOLONE HEXACETONIDE	4	1