Osteofibrous dysplasia

Summary

Osteofibrous dysplasia (MONDO:0011806) is a disease with 1 cohort gene and 1 clinical trial.

At a glance

• Cohort genes: 1
• ClinVar variants: 83
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	osteofibrous dysplasia
Mondo ID	MONDO:0011806
MeSH	C563276, C563787
OMIM	607278, 609143
Orphanet	488265
NCIT	C53970
UMLS	C4085248
MedGen	895748
GARD	0010887
Is cancer (heuristic)	no

Also known as: cortical fibrous dysplasia · Kempson-Campanacci lesion · OFD · OSFD · ossifying fibroma of long bones · osteofibrous dysplasia · osteofibrous dysplasia of bone · tibia, bowing of, with pseudarthrosis and pectus excavatum

Data availability: 83 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › osteofibrous dysplasia

Related subtypes (118): osteochondrodysplasia, diaphyseal medullary stenosis-bone malignancy syndrome, fibular aplasia-ectrodactyly syndrome, cerebrocostomandibular syndrome, cleidorhizomelic syndrome, dyschondrosteosis-nephritis syndrome, dysplasia epiphysealis hemimelica, carpotarsal osteochondromatosis, Camurati-Engelmann disease, genochondromatosis, autosomal dominant osteosclerosis, Worth type, coxopodopatellar syndrome, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic dysplasia, parietal foramina with cleidocranial dysplasia, chondromalacia patellae, Currarino triad, Proteus syndrome, brachydactyly-elbow wrist dysplasia syndrome, tricho-dento-osseous syndrome, bird headed-dwarfism, Montreal type, Yunis-Varon syndrome, split hand-foot malformation 1 with sensorineural hearing loss, ghosal hematodiaphyseal dysplasia, hyperostosis corticalis generalisata, Larsen-like syndrome, B3GAT3 type, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal acroscyphodysplasia, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, familial osteodysplasia, Anderson type, pseudodiastrophic dysplasia, rhizomelic syndrome, Urbach type, Richieri Costa-Pereira syndrome, craniometadiaphyseal dysplasia, wormian bone type, Weaver syndrome, SHOX-related short stature, craniofrontonasal syndrome, Eiken syndrome, 2q37 microdeletion syndrome, skeletal dysplasia-epilepsy-short stature syndrome, rhizomelic dysplasia, Patterson-Lowry type, pelvic dysplasia-arthrogryposis of lower limbs syndrome, Marshall-Smith syndrome, baby rattle pelvis dysplasia, metaphyseal dysplasia, Braun-Tinschert type, genitopatellar syndrome, Larsen-like osseous dysplasia-short stature syndrome, pancreatic insufficiency-anemia-hyperostosis syndrome, microcephalic primordial dwarfism due to ZNF335 deficiency, Hartsfield-Bixler-Demyer syndrome, colobomatous microphthalmia-rhizomelic dysplasia syndrome, Tatton-Brown-Rahman overgrowth syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, Catel-Manzke syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, complex lethal osteochondrodysplasia, amniotic band syndrome, metaphyseal anadysplasia, syndromic craniosynostosis, thin ribs-tubular bones-dysmorphism syndrome, dysplasia of head of femur, Meyer type, epimetaphyseal skeletal dysplasia, melorheostosis with osteopoikilosis, Cole-Carpenter syndrome, spondylometaphyseal dysplasia, omodysplasia, Bruck syndrome, osteopetrosis, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, chondroectodermal dysplasia with night blindness, TRPV4-related bone disorder, adactyly of foot, short stature-advanced bone age-early-onset osteoarthritis syndrome, McCune-Albright syndrome, parietal foramina, Sotos syndrome, dysspondyloenchondromatosis, autosomal recessive cutis laxa type 2, FGFR3-related chondrodysplasia, filamin-related bone disorder, short rib dysplasia, spondylodysplastic dysplasia, acromelic dysplasia, bent bone dysplasia, chondrodysplasia punctata, primary osteolysis, non-syndromic limb reduction defect, Robinow syndrome, synpolydactyly, acrocoxomesomelic dysplasia, bone dysplasia Moore type, bone dysplasia corpus callosum agenesis, type 2 collagenopathy, LRP5-related primary osteoporosis, SLC26A2-related skeletal dysplasia, COMP-related skeletal dysplasia, primordial dwarfism and slender bone disorder, polydactyly-syndactyly-triphalangism, lysosomal storage disease with skeletal involvement, abnormal mineralization disorder, calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia, de la Chapelle dysplasia, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, proximal femoral focal deficiency, rhizomelic dysplasia, Ain-Naz type, craniotubular dysplasia, Ikegawa type, TRIP11-related skeletal dysplasia, FAM111A-related skeletal dysplasia

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

83 retrieved; paginated sample, class counts are floors:

44 conflicting classifications of pathogenicity, 31 uncertain significance, 5 benign/likely benign, 1 pathogenic/likely pathogenic, 1 risk factor, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13887	NM_000245.4(MET):c.3281A>G (p.His1094Arg)	MET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225226	NM_000245.4(MET):c.3011_3028+9del	MET	risk factor	no assertion criteria provided
1021858	NM_000245.4(MET):c.3403A>T (p.Ser1135Cys)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1320342	NM_000245.4(MET):c.617T>C (p.Phe206Ser)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134646	NM_000245.4(MET):c.103A>T (p.Met35Leu)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135966	NM_000245.4(MET):c.3218C>T (p.Pro1073Leu)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
142059	NM_000245.4(MET):c.406G>A (p.Val136Ile)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
184358	NM_000245.4(MET):c.1669A>G (p.Thr557Ala)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
185606	NM_000245.4(MET):c.1081G>T (p.Ala361Ser)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
186678	NM_000245.4(MET):c.2825C>T (p.Ser942Leu)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
188364	NM_000245.4(MET):c.1132G>A (p.Val378Ile)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216513	NM_000245.4(MET):c.632T>G (p.Leu211Trp)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
219422	NM_000245.4(MET):c.2555T>A (p.Met852Lys)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220057	NM_000245.4(MET):c.4145G>A (p.Arg1382Gln)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246627	NM_000245.4(MET):c.1853C>T (p.Thr618Met)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
252899	NM_000245.4(MET):c.1336A>G (p.Ile446Val)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
358684	NM_000245.4(MET):c.1174C>A (p.Pro392Thr)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411906	NM_000245.4(MET):c.4150G>A (p.Ala1384Thr)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411909	NM_000245.4(MET):c.143C>G (p.Ala48Gly)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411912	NM_000245.4(MET):c.2318C>T (p.Pro773Leu)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
411918	NM_000245.4(MET):c.2971C>T (p.Pro991Ser)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41623	NM_000245.4(MET):c.2908C>T (p.Arg970Cys)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41624	NM_000245.4(MET):c.2975C>T (p.Thr992Ile)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41627	NM_000245.4(MET):c.504G>T (p.Glu168Asp)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
41630	NM_000245.4(MET):c.967A>G (p.Ser323Gly)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
454188	NM_000245.4(MET):c.142G>A (p.Ala48Thr)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
454219	NM_000245.4(MET):c.2684C>T (p.Thr895Met)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
480824	NM_000245.4(MET):c.803C>T (p.Thr268Ile)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
485734	NM_000245.4(MET):c.818C>A (p.Thr273Asn)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
485750	NM_000245.4(MET):c.4090C>T (p.Pro1364Ser)	MET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 5 · 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
MET	Supportive	Autosomal dominant	osteofibrous dysplasia	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MET	Orphanet:319298	Papillary renal cell carcinoma
MET	Orphanet:33402	Pediatric hepatocellular carcinoma
MET	Orphanet:47044	Hereditary papillary renal cell carcinoma
MET	Orphanet:488265	Osteofibrous dysplasia
MET	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
MET	HGNC:7029	ENSG00000105976	P08581	Hepatocyte growth factor receptor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MET	Hepatocyte growth factor receptor	Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Semap_dom

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
germinal epithelium of ovary	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MET	270	ubiquitous	marker	pigmented layer of retina, germinal epithelium of ovary, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MET	5,823

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MET	P08581	130

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. 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
Drug-mediated inhibition of MET activation	1	5710.0×	0.004	MET
MET activates STAT3	1	3806.7×	0.004	MET
MET activates PTPN11	1	2284.0×	0.004	MET
MET interacts with TNS proteins	1	2284.0×	0.004	MET
MET Receptor Activation	1	1903.3×	0.004	MET
MET activates PI3K/AKT signaling	1	1903.3×	0.004	MET
Sema4D mediated inhibition of cell attachment and migration	1	1427.5×	0.004	MET
MET receptor recycling	1	1142.0×	0.004	MET
MET activates RAS signaling	1	1038.2×	0.004	MET
MET activates RAP1 and RAC1	1	1038.2×	0.004	MET
Listeria monocytogenes entry into host cells	1	1038.2×	0.004	MET
InlB-mediated entry of Listeria monocytogenes into host cell	1	761.3×	0.005	MET
Sema4D in semaphorin signaling	1	671.8×	0.005	MET
MET promotes cell motility	1	601.0×	0.005	MET
MECP2 regulates neuronal receptors and channels	1	601.0×	0.005	MET
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	571.0×	0.005	MET
Negative regulation of MET activity	1	519.1×	0.005	MET
Semaphorin interactions	1	393.8×	0.006	MET
MET activates PTK2 signaling	1	380.7×	0.006	MET
PI3K/AKT Signaling in Cancer	1	368.4×	0.006	MET
Bacterial Infection Pathways	1	335.9×	0.006	MET
Signaling by MET	1	317.2×	0.006	MET
Transcriptional Regulation by MECP2	1	317.2×	0.006	MET
Negative regulation of the PI3K/AKT network	1	278.5×	0.007	MET
MITF-M-dependent gene expression	1	181.3×	0.010	MET
MAPK1/MAPK3 signaling	1	131.3×	0.013	MET
Constitutive Signaling by Aberrant PI3K in Cancer	1	126.9×	0.013	MET
MITF-M-regulated melanocyte development	1	114.2×	0.014	MET
MAPK family signaling cascades	1	102.9×	0.015	MET
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	96.8×	0.015	MET

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
negative regulation of hydrogen peroxide-mediated programmed cell death	1	4213.0×	0.003	MET
hepatocyte growth factor receptor signaling pathway	1	2106.5×	0.003	MET
endothelial cell morphogenesis	1	1053.2×	0.003	MET
positive regulation of endothelial cell chemotaxis	1	991.3×	0.003	MET
positive chemotaxis	1	802.5×	0.003	MET
branching morphogenesis of an epithelial tube	1	732.7×	0.003	MET
pancreas development	1	674.1×	0.003	MET
excitatory postsynaptic potential	1	443.5×	0.004	MET
semaphorin-plexin signaling pathway	1	401.2×	0.004	MET
negative regulation of autophagy	1	259.3×	0.006	MET
liver development	1	221.7×	0.006	MET
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.007	MET
neuron differentiation	1	100.3×	0.012	MET
cell surface receptor signaling pathway	1	64.1×	0.017	MET
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	MET

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MET	AFATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MET	95	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AFATINIB	4	MET
FEDRATINIB	4	MET
TIVOZANIB	4	MET
AXITINIB	4	MET
SORAFENIB	4	MET
NERATINIB	4	MET
INFIGRATINIB PHOSPHATE	4	MET
INFIGRATINIB	4	MET
PALBOCICLIB	4	MET
ENTRECTINIB	4	MET
DABRAFENIB	4	MET
CABOZANTINIB S-MALATE	4	MET
AFATINIB DIMALEATE	4	MET
CABOZANTINIB	4	MET
CERITINIB	4	MET
VANDETANIB	4	MET
BOSUTINIB	4	MET
CAPMATINIB	4	MET
TEPOTINIB	4	MET
BRIGATINIB	4	MET
ENSARTINIB	4	MET
PAZOPANIB	4	MET
NINTEDANIB	4	MET
SUNITINIB	4	MET
ERLOTINIB	4	MET
CRIZOTINIB	4	MET
MIDOSTAURIN	4	MET
GEFITINIB	4	MET
LINSITINIB	3	MET
RIGOSERTIB	3	MET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MET	2,015	Binding:2005, Functional:6, ADMET:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MET	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MET	2,015

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

30 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.

Compound	Max phase	Cohort target (bioactivity)
AFATINIB	4	MET
FEDRATINIB	4	MET
TIVOZANIB	4	MET
AXITINIB	4	MET
SORAFENIB	4	MET
NERATINIB	4	MET
INFIGRATINIB PHOSPHATE	4	MET
INFIGRATINIB	4	MET
PALBOCICLIB	4	MET
ENTRECTINIB	4	MET
DABRAFENIB	4	MET
CABOZANTINIB S-MALATE	4	MET
AFATINIB DIMALEATE	4	MET
CABOZANTINIB	4	MET
CERITINIB	4	MET
VANDETANIB	4	MET
BOSUTINIB	4	MET
CAPMATINIB	4	MET
TEPOTINIB	4	MET
BRIGATINIB	4	MET
ENSARTINIB	4	MET
PAZOPANIB	4	MET
NINTEDANIB	4	MET
SUNITINIB	4	MET
ERLOTINIB	4	MET
CRIZOTINIB	4	MET
MIDOSTAURIN	4	MET
GEFITINIB	4	MET
LINSITINIB	3	MET
RIGOSERTIB	3	MET

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MET
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	0

Undrugged target profiles

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

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
NCT04104763	Not specified	COMPLETED	Osteofibrous Dysplasia (Kempson-Campanacci’s Disease)