Blau syndrome

Summary

Blau syndrome (MONDO:0008523) is a disease caused by NOD2 (GenCC Definitive), with 3 cohort genes and 9 clinical trials. Top therapeutic interventions include tofacitinib.

At a glance

• Prevalence: <1 / 1 000 000 (Denmark) [Orphanet-validated]
• Causal gene: NOD2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 1,111
• Phenotypes (HPO): 46
• Clinical trials: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	<1 / 1 000 000	0.06	Denmark	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0000491	Keratitis	Very frequent (80-99%)
HP:0000953	Hyperpigmentation of the skin	Very frequent (80-99%)
HP:0000988	Skin rash	Very frequent (80-99%)
HP:0001094	Iridocyclitis	Very frequent (80-99%)
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0001386	Joint swelling	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0005764	Polyarticular arthritis	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0012123	Posterior uveitis	Very frequent (80-99%)
HP:0012647	Abnormal inflammatory response	Very frequent (80-99%)
HP:0100769	Synovitis	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000958	Dry skin	Frequent (30-79%)
HP:0001369	Arthritis	Frequent (30-79%)
HP:0001945	Fever	Frequent (30-79%)
HP:0012219	Erythema nodosum	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000112	Nephropathy	Occasional (5-29%)
HP:0000217	Xerostomia	Occasional (5-29%)
HP:0000488	Retinopathy	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0000587	Abnormal optic nerve morphology	Occasional (5-29%)
HP:0000610	Abnormal choroid morphology	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0001291	Abnormal cranial nerve morphology	Occasional (5-29%)
HP:0001392	Abnormality of the liver	Occasional (5-29%)
HP:0001701	Pericarditis	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002716	Lymphadenopathy	Occasional (5-29%)
HP:0003774	Stage 5 chronic kidney disease	Occasional (5-29%)
HP:0004942	Aortic aneurysm	Occasional (5-29%)
HP:0005310	Large vessel vasculitis	Occasional (5-29%)
HP:0006770	Clear cell renal cell carcinoma	Occasional (5-29%)
HP:0008046	Abnormal retinal vascular morphology	Occasional (5-29%)
HP:0008064	Ichthyosis	Occasional (5-29%)
HP:0010286	Abnormal salivary gland morphology	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)
HP:0100654	Retrobulbar optic neuritis	Occasional (5-29%)
HP:0200042	Skin ulcer	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Blau syndrome
Mondo ID	MONDO:0008523
MeSH	C538157
OMIM	186580, 609464
Orphanet	90340, 90341
DOID	DOID:0050678
ICD-11	382488319
NCIT	C116794
SNOMED CT	699861000
UMLS	C5201146
MedGen	1684759
GARD	0000304
MedDRA	10071755
Is cancer (heuristic)	no

Also known as: ACUG · arthrocutaneouveal granulomatosis · Blau syndrome · BLAUS · early-onset sarcoidosis · EOS · granulomatosis, familial juvenile systemic · granulomatosis, familial, Blau type · granulomatous inflammatory arthritis, dermatitis, and uveitis, familial · Jabs syndrome · paediatric granulomatous arthritis · pediatric granulomatous arthritis · sarcoidosis, early-onset · synovitis granulomatous with uveitis and cranial neuropathies

Data availability: 1,111 ClinVar variants · 6 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › autoinflammatory syndrome › sarcoidosis › Blau syndrome

Related subtypes (7): cardiac sarcoidosis, pulmonary sarcoidosis, hypercalcemic sarcoidosis, skin sarcoidosis, uveoparotid fever, Löfgren syndrome, neurosarcoidosis

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

600 retrieved; paginated sample, class counts are floors:

304 uncertain significance, 199 likely benign, 65 conflicting classifications of pathogenicity, 19 benign/likely benign, 11 benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2921502	NM_001370466.1(NOD2):c.1068G>C (p.Glu356Asp)	NOD2	Pathogenic	criteria provided, single submitter
1184615	NM_001370466.1(NOD2):c.1390A>C (p.Met464Leu)	NOD2	Likely pathogenic	no assertion criteria provided
2170482	NM_001370466.1(NOD2):c.2948A>G (p.Asn983Ser)	CYLD-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319475	NM_001370466.1(NOD2):c.3013G>A (p.Gly1005Ser)	CYLD-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319476	NM_001370466.1(NOD2):c.*89C>T	CYLD-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319484	NM_001370466.1(NOD2):c.*462C>A	CYLD-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
319488	NM_001370466.1(NOD2):c.*873C>T	CYLD-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001128	NM_001370466.1(NOD2):c.299C>T (p.Ser100Leu)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1008353	NM_001370466.1(NOD2):c.2298G>A (p.Val766=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
103114	NM_001370466.1(NOD2):c.*8G>A	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1043683	NM_001370466.1(NOD2):c.1088A>T (p.Asp363Val)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1077583	NM_001370466.1(NOD2):c.2767A>C (p.Met923Leu)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1095325	NM_001370466.1(NOD2):c.1898C>G (p.Ala633Gly)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1095701	NM_001370466.1(NOD2):c.873A>C (p.Ala291=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1097717	NM_001370466.1(NOD2):c.1182G>A (p.Lys394=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1101089	NM_001370466.1(NOD2):c.2304G>C (p.Leu768=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1134828	NM_001370466.1(NOD2):c.1462C>T (p.Leu488=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1156906	NM_001370466.1(NOD2):c.1677G>T (p.Val559=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1165567	NM_001370466.1(NOD2):c.2381+7G>T	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1349073	NM_001370466.1(NOD2):c.2828A>G (p.Glu943Gly)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1391926	NM_001370466.1(NOD2):c.1709C>T (p.Ala570Val)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1453223	NM_001370466.1(NOD2):c.1717G>A (p.Glu573Lys)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1484179	NM_001370466.1(NOD2):c.1234C>T (p.Arg412Cys)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1539777	NM_001370466.1(NOD2):c.2595C>T (p.Ala865=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1540609	NM_001370466.1(NOD2):c.2619C>T (p.Ser873=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1648109	NM_001370466.1(NOD2):c.162C>T (p.Leu54=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1671086	NM_001370466.1(NOD2):c.2177G>A (p.Arg726Gln)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1675106	NM_001370466.1(NOD2):c.963A>G (p.Leu321=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694105	NM_001370466.1(NOD2):c.1605C>T (p.Cys535=)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694108	NM_001370466.1(NOD2):c.2024G>A (p.Arg675Gln)	NOD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
NOD2	Definitive	Autosomal dominant	Blau syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NOD2	Orphanet:90340	Blau syndrome
CYLD	Orphanet:211	Familial cylindromatosis
CYLD	Orphanet:867	Familial multiple trichoepithelioma

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NOD2	HGNC:5331	ENSG00000167207	Q9HC29	Nucleotide-binding oligomerization domain-containing protein 2	gencc,clinvar
CYLD	HGNC:2584	ENSG00000083799	Q9NQC7	Ubiquitin carboxyl-terminal hydrolase CYLD	clinvar
CYLD-AS1	HGNC:55352	ENSG00000261644		CYLD antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NOD2	Nucleotide-binding oligomerization domain-containing protein 2	Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity.
CYLD	Ubiquitin carboxyl-terminal hydrolase CYLD	Deubiquitinase that specifically cleaves ‘Lys-63’- and linear ‘Met-1’-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-induced necroptosis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Protease	1	12.2×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NOD2	Other/Unknown	no		CARD, Leu-rich_rpt, NACHT_NTPase
CYLD	Protease	yes		CAP-Gly_domain, Peptidase_C19_UCH, USP_CS
CYLD-AS1	Other/Unknown	no

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
leukocyte	2
monocyte	2
mononuclear cell	1
calcaneal tendon	1
lateral nuclear group of thalamus	1
lymph node	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NOD2	189	broad	marker	monocyte, mononuclear cell, leukocyte
CYLD	294	ubiquitous	marker	lateral nuclear group of thalamus, calcaneal tendon, lymph node
CYLD-AS1	126		yes	granulocyte, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOD2	3,527
CYLD	3,507
CYLD-AS1	0

Intra-cohort edges

A	B	Sources
CYLD	NOD2	biogrid_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CYLD	Q9NQC7	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NOD2	Q9HC29	84.76

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
NOD1/2 Signaling Pathway	2	317.2×	1e-04	NOD2, CYLD
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	259.6×	0.011	NOD2
activated TAK1 mediates p38 MAPK activation	1	248.3×	0.011	NOD2
TNFR1-induced proapoptotic signaling	1	219.6×	0.011	CYLD
TNFR1-induced NF-kappa-B signaling pathway	1	167.9×	0.011	CYLD
Negative regulators of DDX58/IFIH1 signaling	1	163.1×	0.011	CYLD
TAK1-dependent IKK and NF-kappa-B activation	1	150.3×	0.011	NOD2
Ovarian tumor domain proteases	1	139.3×	0.011	NOD2
Regulation of TNFR1 signaling	1	112.0×	0.012	CYLD
Interleukin-1 signaling	1	62.1×	0.019	NOD2
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.024	NOD2
Ub-specific processing proteases	1	26.6×	0.037	CYLD

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
detection of muramyl dipeptide	1	8426.0×	0.002	NOD2
positive regulation of gamma-delta T cell activation	1	8426.0×	0.002	NOD2
negative regulation of interleukin-18-mediated signaling pathway	1	8426.0×	0.002	CYLD
regulation of inflammatory response	2	168.5×	0.002	NOD2, CYLD
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	2808.7×	0.004	CYLD
ripoptosome assembly involved in necroptotic process	1	2808.7×	0.004	CYLD
protein linear deubiquitination	1	2808.7×	0.004	CYLD
detection of biotic stimulus	1	2106.5×	0.004	NOD2
positive regulation of dendritic cell cytokine production	1	1685.2×	0.004	NOD2
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	1404.3×	0.004	CYLD
cellular response to peptidoglycan	1	1404.3×	0.004	NOD2
negative regulation of macrophage apoptotic process	1	1404.3×	0.004	NOD2
positive regulation of dendritic cell antigen processing and presentation	1	1203.7×	0.004	NOD2
positive regulation of type 2 immune response	1	1203.7×	0.004	NOD2
intestinal stem cell homeostasis	1	1203.7×	0.004	NOD2
regulation of intrinsic apoptotic signaling pathway	1	1203.7×	0.004	CYLD
positive regulation of B cell activation	1	1053.2×	0.004	NOD2
positive regulation of protein K63-linked ubiquitination	1	1053.2×	0.004	NOD2
negative regulation of p38MAPK cascade	1	1053.2×	0.004	CYLD
innate immune response	2	33.6×	0.004	NOD2, CYLD
regulation of necroptotic process	1	936.2×	0.004	CYLD
regulation of appetite	1	842.6×	0.004	NOD2
cellular response to muramyl dipeptide	1	842.6×	0.004	NOD2
host-mediated modulation of intestinal microbiota composition	1	766.0×	0.004	NOD2
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	766.0×	0.004	NOD2
antibacterial innate immune response	1	766.0×	0.004	NOD2
detection of bacterium	1	702.2×	0.004	NOD2
response to muramyl dipeptide	1	702.2×	0.004	NOD2
positive regulation of protein localization	1	702.2×	0.004	CYLD
regulation of B cell differentiation	1	648.1×	0.004	CYLD

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
NOD2	PACLITAXEL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOD2	6	4
CYLD	0	0
CYLD-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PACLITAXEL	4	NOD2
DOCETAXEL ANHYDROUS	4	NOD2
GEFITINIB	4	NOD2
CYCLOVALONE	2	NOD2
MURAMYL DIPEPTIDE	1	NOD2
PD-0166285	1	NOD2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOD2	126	Binding:121, Functional:5
CYLD	3	Binding:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NOD2	126

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

6 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)
PACLITAXEL	4	NOD2
DOCETAXEL ANHYDROUS	4	NOD2
GEFITINIB	4	NOD2
CYCLOVALONE	2	NOD2
MURAMYL DIPEPTIDE	1	NOD2
PD-0166285	1	NOD2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NOD2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CYLD
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CYLD-AS1

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)
CYLD	3	—
CYLD-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 9.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	7
PHASE4	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06660329	PHASE4	ENROLLING_BY_INVITATION	Efficacy and Safety of Tofacitinib in Refractory Blau Syndrome
NCT06206811	PHASE1	COMPLETED	Phase 1 Study to Investigate OD-07656 in Healthy Adult Participants
NCT00001244	Not specified	RECRUITING	Immune Regulation in Patients With Common Variable Immunodeficiency and Related Inborn Errors of Immunity (IEI)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06245993	Not specified	RECRUITING	Study of Residuals Deformities After Diaphyseal Femoral Fracture in Children Treated by Skin Traction
NCT06527924	Not specified	NOT_YET_RECRUITING	A Randomized Study on Sagittal Angle Differences in Lower Limbs Between Normal Individuals and Osteoarthritis Patients
NCT06688838	Not specified	ENROLLING_BY_INVITATION	Effective Treatment of Jak1/3 Inhibitor in Blau Syndrome
NCT05224908	Not specified	COMPLETED	Breech Pelvimetry by EOS® Technique With Change of Maternal Position and Delivery Route
NCT05274776	Not specified	UNKNOWN	Safely Reduce Newborn Antibiotic Exposure With the Early-onset Sepsis Calculator

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TOFACITINIB	4	1