Sterile multifocal osteomyelitis with periostitis and pustulosis

Summary

Sterile multifocal osteomyelitis with periostitis and pustulosis (MONDO:0013021) is a disease caused by IL1RN (GenCC Strong), with 3 cohort genes and 2 clinical trials. Top therapeutic interventions include rilonacept.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IL1RN (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 197
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	sterile multifocal osteomyelitis with periostitis and pustulosis
Mondo ID	MONDO:0013021
MeSH	C557815
OMIM	612852
Orphanet	210115
DOID	DOID:0061225
NCIT	C119056
UMLS	C2748507
MedGen	411230
GARD	0010516
Is cancer (heuristic)	no

Also known as: autoinflammatory disease due to interleukin-1 receptor antagonist deficiency · deficiency of interleukin-1 receptor antagonist · deficiency of the Interleukin-1 receptor antagonist · DIRA · Interleukin-1 receptor antagonist deficiency · OMPP · osteomyelitis, STERILE multifocal, with periostitis and pustulosis

Data availability: 197 ClinVar variants · 5 GenCC gene-disease records.

Disease family

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 › sterile multifocal osteomyelitis with periostitis and pustulosis

Related subtypes (2): Majeed syndrome, 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

197 retrieved; paginated sample, class counts are floors:

80 uncertain significance, 70 likely benign, 16 benign, 13 conflicting classifications of pathogenicity, 11 pathogenic, 5 benign/likely benign, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14675	NM_173842.3(IL1RN):c.229G>T (p.Glu77Ter)	IL1RN	Pathogenic	criteria provided, multiple submitters, no conflicts
14676	NM_173842.3(IL1RN):c.160C>T (p.Gln54Ter)	IL1RN	Pathogenic	no assertion criteria provided
14678	NC_000002.12:g.112960554_113135775del	IL1RN	Pathogenic	no assertion criteria provided
1942385	NM_173842.3(IL1RN):c.133C>T (p.Gln45Ter)	IL1RN	Pathogenic	criteria provided, single submitter
2731291	NM_173841.3(IL1RN):c.52G>T (p.Glu18Ter)	IL1RN	Pathogenic	criteria provided, single submitter
2821013	NM_173841.3(IL1RN):c.25G>T (p.Glu9Ter)	IL1RN	Pathogenic	criteria provided, single submitter
3247349	NC_000002.11:g.(?113875596)(113875625_?)del	IL1RN	Pathogenic	criteria provided, single submitter
660820	NM_173842.3(IL1RN):c.213_227del (p.Asp72_Ile76del)	IL1RN	Pathogenic	criteria provided, single submitter
832163	NC_000002.12:g.(?113116893)(113135016_?)del	IL1RN	Pathogenic	criteria provided, single submitter
97905	NM_173842.3(IL1RN):c.156_157del (p.Asn52fs)	IL1RN	Pathogenic	criteria provided, single submitter
1459348	NC_000002.11:g.(?113817016)(113890448_?)del	IL36RN	Pathogenic	criteria provided, single submitter
3069200	NM_173842.3(IL1RN):c.46del (p.Leu16fs)	IL1RN	Likely pathogenic	criteria provided, single submitter
559539	NM_173842.3(IL1RN):c.63A>G (p.Ser21=)	IL1RN	Likely pathogenic	criteria provided, single submitter
1107434	NM_173841.3(IL1RN):c.66C>T (p.Asp22=)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1121683	NM_173842.3(IL1RN):c.336C>T (p.Asp112=)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1443020	NM_173842.3(IL1RN):c.241C>G (p.Leu81Val)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694279	NM_173842.3(IL1RN):c.207A>G (p.Glu69=)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694280	NM_173842.3(IL1RN):c.288G>A (p.Lys96=)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330826	NM_173842.3(IL1RN):c.318+12C>G	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330829	NM_173842.3(IL1RN):c.529G>A (p.Glu177Lys)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330833	NM_173842.3(IL1RN):c.*162C>T	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
470170	NM_173842.3(IL1RN):c.370G>A (p.Ala124Thr)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
735122	NM_173842.3(IL1RN):c.414T>C (p.Ser138=)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
752447	NM_173842.3(IL1RN):c.117-9C>T	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
753684	NM_173842.3(IL1RN):c.495C>T (p.Gly165=)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
797505	NM_173842.3(IL1RN):c.192T>C (p.Asn64=)	IL1RN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002121	NM_173842.3(IL1RN):c.449T>C (p.Met150Thr)	IL1RN	Uncertain significance	criteria provided, single submitter
1004657	NM_173842.3(IL1RN):c.318+3A>G	IL1RN	Uncertain significance	criteria provided, single submitter
1005039	NM_173842.3(IL1RN):c.526G>A (p.Asp176Asn)	IL1RN	Uncertain significance	criteria provided, single submitter
1006607	NM_173842.3(IL1RN):c.267G>C (p.Lys89Asn)	IL1RN	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 9 · 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
IL1RN	Strong	Autosomal recessive	sterile multifocal osteomyelitis with periostitis and pustulosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL1RN	Orphanet:210115	Sterile multifocal osteomyelitis with periostitis and pustulosis
IL36RN	Orphanet:163927	Pustulosis palmaris et plantaris
IL36RN	Orphanet:163931	Acrodermatitis continua of Hallopeau
IL36RN	Orphanet:247353	Generalized pustular psoriasis
IL36RN	Orphanet:404546	DITRA
NFKBIA	Orphanet:150	Nasopharyngeal carcinoma
NFKBIA	Orphanet:251576	Gliosarcoma
NFKBIA	Orphanet:251579	Giant cell glioblastoma
NFKBIA	Orphanet:98813	Hypohidrotic ectodermal dysplasia with immunodeficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL1RN	HGNC:6000	ENSG00000136689	P18510	Interleukin-1 receptor antagonist protein	gencc,clinvar
IL36RN	HGNC:15561	ENSG00000136695	Q9UBH0	Interleukin-36 receptor antagonist protein	clinvar
NFKBIA	HGNC:7797	ENSG00000100906	P25963	NF-kappa-B inhibitor alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL1RN	Interleukin-1 receptor antagonist protein	Anti-inflammatory antagonist of interleukin-1 family of proinflammatory cytokines such as interleukin-1beta/IL1B and interleukin-1alpha/IL1A.
IL36RN	Interleukin-36 receptor antagonist protein	Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling.
NFKBIA	NF-kappa-B inhibitor alpha	Inhibits the activity of dimeric NF-kappa-B/REL complexes by trapping REL (RELA/p65 and NFKB1/p50) dimers in the cytoplasm by masking their nuclear localization signals.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL1RN	Other/Unknown	no		IL-1_fam, IL-1RA/IL-36, IL1/FGF
IL36RN	Other/Unknown	no		IL-1_fam, IL-1RA/IL-36, IL1/FGF
NFKBIA	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, NF-kappa-B_inhibitor

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
lower esophagus mucosa	1
palpebral conjunctiva	1
amniotic fluid	1
gingiva	1
upper arm skin	1
lower lobe of lung	1
pericardium	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL1RN	220	broad	marker	lower esophagus mucosa, buccal mucosa cell, palpebral conjunctiva
IL36RN	106	tissue_specific	yes	amniotic fluid, upper arm skin, gingiva
NFKBIA	302	ubiquitous	marker	vena cava, pericardium, lower lobe of lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NFKBIA	6,991
IL1RN	2,550
IL36RN	1,137

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IL1RN	P18510	5
NFKBIA	P25963	5
IL36RN	Q9UBH0	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-1 signaling	2	82.8×	0.003	IL1RN, NFKBIA
IkBA variant leads to EDA-ID	1	543.8×	0.010	NFKBIA
Interleukin-36 pathway	1	543.8×	0.010	IL36RN
SUMOylation of immune response proteins	1	317.2×	0.011	NFKBIA
NF-kB is activated and signals survival	1	292.8×	0.011	NFKBIA
Dengue virus modulates apoptosis	1	237.9×	0.011	NFKBIA
RIP-mediated NFkB activation via ZBP1	1	223.9×	0.011	NFKBIA
TRAF6 mediated NF-kB activation	1	152.3×	0.014	NFKBIA
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	119.0×	0.016	NFKBIA
TAK1-dependent IKK and NF-kappa-B activation	1	100.2×	0.017	NFKBIA
SARS-CoV-1 activates/modulates innate immune responses	1	90.6×	0.017	NFKBIA
Interleukin-10 signaling	1	77.7×	0.018	IL1RN
Activation of NF-kappaB in B cells	1	65.6×	0.020	NFKBIA
FCERI mediated NF-kB activation	1	52.1×	0.023	NFKBIA
CLEC7A (Dectin-1) signaling	1	47.6×	0.024	NFKBIA
Downstream TCR signaling	1	42.8×	0.025	NFKBIA
Ub-specific processing proteases	1	17.7×	0.055	NFKBIA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 cholesterol transport	1	1404.3×	0.008	NFKBIA
antifungal humoral response	1	1123.5×	0.008	IL36RN
nucleotide-binding oligomerization domain containing 1 signaling pathway	1	1123.5×	0.008	NFKBIA
negative regulation of cytokine-mediated signaling pathway	1	624.1×	0.008	IL36RN
negative regulation of heterotypic cell-cell adhesion	1	624.1×	0.008	IL1RN
negative regulation of interleukin-1-mediated signaling pathway	1	561.7×	0.008	IL1RN
negative regulation of lipid storage	1	510.7×	0.008	NFKBIA
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	510.7×	0.008	NFKBIA
response to muramyl dipeptide	1	468.1×	0.008	NFKBIA
negative regulation of macrophage derived foam cell differentiation	1	432.1×	0.008	NFKBIA
immune response	2	31.4×	0.008	IL1RN, IL36RN
inflammatory response	2	25.1×	0.008	IL1RN, IL36RN
negative regulation of interleukin-17 production	1	351.1×	0.009	IL36RN
cellular response to cold	1	351.1×	0.009	NFKBIA
negative regulation of protein import into nucleus	1	312.1×	0.009	NFKBIA
negative regulation of myeloid cell differentiation	1	312.1×	0.009	NFKBIA
non-canonical NF-kappaB signal transduction	1	280.9×	0.009	NFKBIA
interleukin-1-mediated signaling pathway	1	267.5×	0.009	NFKBIA
response to muscle stretch	1	255.3×	0.009	NFKBIA
lipopolysaccharide-mediated signaling pathway	1	175.5×	0.011	NFKBIA
toll-like receptor 4 signaling pathway	1	175.5×	0.011	NFKBIA
response to exogenous dsRNA	1	175.5×	0.011	NFKBIA
insulin secretion	1	144.0×	0.012	IL1RN
negative regulation of Notch signaling pathway	1	144.0×	0.012	NFKBIA
acute-phase response	1	140.4×	0.012	IL1RN
negative regulation of cytokine production involved in inflammatory response	1	140.4×	0.012	NFKBIA
B cell receptor signaling pathway	1	133.8×	0.012	NFKBIA
negative regulation of type II interferon production	1	127.7×	0.012	IL36RN
canonical NF-kappaB signal transduction	1	122.1×	0.012	NFKBIA
obsolete negative regulation of NF-kappaB transcription factor activity	1	119.5×	0.012	NFKBIA

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IL1RN	0	0
IL36RN	0	0
NFKBIA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NFKBIA	48	Binding:48
IL1RN	26	Binding:26

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	IL1RN, IL36RN, NFKBIA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IL1RN	26	—
IL36RN	0	—
NFKBIA	48	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01801449	PHASE2	COMPLETED	Rilonacept for Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)
NCT02974595	Not specified	RECRUITING	Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases (NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still’S-like Diseases, and Other Undifferentiated Autoinflammatory Diseases)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RILONACEPT	4	1