Chronic recurrent multifocal osteomyelitis

Summary

Chronic recurrent multifocal osteomyelitis (MONDO:0009813) is a disease with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include etanercept, golimumab, and leflunomide.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 27
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2.5	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.3	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002754	Osteomyelitis	Very frequent (80-99%)
HP:0100774	Hyperostosis	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Frequent (30-79%)
HP:0000969	Edema	Frequent (30-79%)
HP:0001369	Arthritis	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002797	Osteolysis	Frequent (30-79%)
HP:0003468	Abnormal vertebral morphology	Frequent (30-79%)
HP:0003565	Elevated erythrocyte sedimentation rate	Frequent (30-79%)
HP:0004396	Poor appetite	Frequent (30-79%)
HP:0005464	Craniofacial osteosclerosis	Frequent (30-79%)
HP:0005930	Abnormality of epiphysis morphology	Frequent (30-79%)
HP:0011227	Elevated circulating C-reactive protein concentration	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0000988	Skin rash	Occasional (5-29%)
HP:0000989	Pruritus	Occasional (5-29%)
HP:0001061	Acne	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002037	Inflammation of the large intestine	Occasional (5-29%)
HP:0002633	Vasculitis	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003765	Psoriasiform dermatitis	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)
HP:0100781	Abnormality of the sacroiliac joint	Occasional (5-29%)
HP:0100847	Palmoplantar pustulosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	chronic recurrent multifocal osteomyelitis
Mondo ID	MONDO:0009813
MeSH	C535456
OMIM	609628
Orphanet	324964
DOID	DOID:0060645
ICD-10-CM	M86.3
ICD-11	1256384247
NCIT	C119042
SNOMED CT	240151005
UMLS	C0410422
MedGen	140822
GARD	0006108
Is cancer (heuristic)	no

Also known as: chronic multifocal osteomyelitis · chronic recurrent multifocal osteomyelitis · chronic recurrent multifocal osteomyelitis (disease) · CMO · CNO/CRMO · CRMO · multifocal osteomyelitis, chronic · NBO · non-bacterial osteomyelitis

Data availability: 2 ClinVar variants · 1 HPO phenotype.

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 inflammation disease › osteomyelitis › chronic recurrent multifocal osteomyelitis

Related subtypes (1): petrositis

Subtypes (3): Majeed syndrome, sterile multifocal osteomyelitis with periostitis and pustulosis, chronic recurrent multifocal osteomyelitis 3

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

2 retrieved; paginated sample, class counts are floors:

2 association

ClinVar	Variant (HGVS)	Gene	Classification	Review
973943	NM_152649.4(MLKL):c.394T>C (p.Ser132Pro)	MLKL	association	no assertion criteria provided
973944	NM_152649.4(MLKL):c.437G>A (p.Arg146Gln)	MLKL	association	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

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

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
MLKL	HGNC:26617	ENSG00000168404	Q8NB16	Mixed lineage kinase domain-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MLKL	Mixed lineage kinase domain-like protein	Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process.

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)
MLKL	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Kinase-like_dom_sf

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
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MLKL	234	ubiquitous	marker	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MLKL	2,090

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MLKL	Q8NB16	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. 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
Microbial modulation of RIPK1-mediated regulated necrosis	1	2855.0×	0.003	MLKL
Defective RIPK1-mediated regulated necrosis	1	1903.3×	0.003	MLKL
Regulated Necrosis	1	713.8×	0.005	MLKL
Diseases of programmed cell death	1	634.4×	0.005	MLKL
RIPK1-mediated regulated necrosis	1	456.8×	0.005	MLKL
Regulation of necroptotic cell death	1	439.2×	0.005	MLKL
TRP channels	1	407.9×	0.005	MLKL
NS1 Mediated Effects on Host Pathways	1	285.5×	0.006	MLKL
Programmed Cell Death	1	146.4×	0.010	MLKL
Stimuli-sensing channels	1	135.9×	0.010	MLKL
Ion channel transport	1	96.0×	0.012	MLKL
Transport of small molecules	1	25.1×	0.043	MLKL
Disease	1	13.1×	0.076	MLKL

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
execution phase of necroptosis	1	8426.0×	7e-04	MLKL
necroptotic signaling pathway	1	2106.5×	0.001	MLKL
necroptotic process	1	1053.2×	0.002	MLKL
protein homotrimerization	1	991.3×	0.002	MLKL
defense response to virus	1	69.3×	0.016	MLKL
cell surface receptor signaling pathway	1	64.1×	0.016	MLKL

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
MLKL	CRIZOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MLKL	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRIZOTINIB	4	MLKL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MLKL	112	Binding:112

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MLKL	112

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

1 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)
CRIZOTINIB	4	MLKL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MLKL
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: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04725422	Not specified	RECRUITING	CHronic Nonbacterial Osteomyelitis International Registry
NCT07483853	Not specified	RECRUITING	Reliability and Validation of the WB-MRI Radiological Score in CRMO
NCT03433287	Not specified	UNKNOWN	Chronic Recurrent Multifocal Osteomyelitis - a Bacterial Cause?
NCT05103137	Not specified	COMPLETED	Post-transition Clinical and Socio-professional Future in Adult Patients With Recurrent Multifocal Chronic Osteitis
NCT06232603	Not specified	TERMINATED	Medication Adherence Intervention in Chronic Recurrent Multifocal Osteomyelitis (CRMO)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ETANERCEPT	4	1
GOLIMUMAB	4	1
LEFLUNOMIDE	4	1
PAMIDRONIC ACID	4	1
SULFASALAZINE	4	1
CERTOLIZUMAB	3	1