CINCA syndrome

Summary

CINCA syndrome (MONDO:0011776) is a disease caused by NLRP3 (GenCC Definitive), with 1 cohort gene and 7 clinical trials. Top therapeutic interventions include canakinumab.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: NLRP3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 256
• Phenotypes (HPO): 44
• Clinical trials: 7

Clinical features

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000538	Pseudopapilledema	Very frequent (80-99%)
HP:0000554	Uveitis	Very frequent (80-99%)
HP:0001025	Urticaria	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001287	Meningitis	Very frequent (80-99%)
HP:0001874	Abnormality of neutrophils	Very frequent (80-99%)
HP:0001911	Abnormality of granulocytes	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002076	Migraine	Very frequent (80-99%)
HP:0002516	Increased intracranial pressure	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003326	Myalgia	Very frequent (80-99%)
HP:0003565	Elevated erythrocyte sedimentation rate	Very frequent (80-99%)
HP:0011227	Elevated circulating C-reactive protein concentration	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0100533	Inflammatory abnormality of the eye	Very frequent (80-99%)
HP:0200034	Papule	Very frequent (80-99%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000969	Edema	Frequent (30-79%)
HP:0001367	Abnormal joint morphology	Frequent (30-79%)
HP:0001373	Joint dislocation	Frequent (30-79%)
HP:0001476	Delayed closure of the anterior fontanelle	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001872	Abnormality of thrombocytes	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0001974	Leukocytosis	Frequent (30-79%)
HP:0002007	Frontal bossing	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002652	Skeletal dysplasia	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000979	Purpura	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001622	Premature birth	Occasional (5-29%)
HP:0002353	EEG abnormality	Occasional (5-29%)
HP:0004349	Reduced bone mineral density	Occasional (5-29%)
HP:0100654	Retrobulbar optic neuritis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	CINCA syndrome
Mondo ID	MONDO:0011776
OMIM	607115
Orphanet	1451
DOID	DOID:0090029
NCIT	C116380
SNOMED CT	239826001
UMLS	C0409818
MedGen	98370
GARD	0001356
NORD	1496
Is cancer (heuristic)	no

Also known as: chronic infantile neurological cutaneous and articular syndrome · chronic neurologic cutaneous and articular syndrome · CINCA · CINCA syndrome · CINCA/NOMID · cryopyrin-associated periodic syndrome 3 · infantile onset multisystem inflammatory disease · infantile-onset multisystem inflammatory disease · IOMID · IOMID syndrome · neonatal onset multisystem inflammatory disease · Neonatal-Onset Multisystem Inflammatory Disease · neonatal-onset multisystem inflammatory disease · NOMID · NOMID syndrome · Prieur Griscelli syndrome · Prieur-Griscelli syndrome

Data availability: 256 ClinVar variants · 5 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › CINCA syndrome

Related subtypes (21): autoimmune disorder of musculoskeletal system, musculoskeletal system benign neoplasm, musculoskeletal system cancer, Klippel-Feil syndrome, enthesopathy, muscle tissue disorder, fasciitis, skeletal system disorder, synovial chondromatosis, auriculoosteodysplasia, hypertrophic osteoarthropathy, primary, autosomal dominant, Upington disease, Ramon syndrome, osteoporosis-oculocutaneous hypopigmentation syndrome, short stature, Brussels type, wormian bone-multiple fractures-dentinogenesis imperfecta-skeletal dysplasia, chondrodysplasia with joint dislocations, gPAPP type, ligament disorder, synovium disorder, disease of the tendon, Short stature, Dauber-Argente type

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

256 retrieved; paginated sample, class counts are floors:

140 uncertain significance, 45 conflicting classifications of pathogenicity, 27 benign/likely benign, 20 benign, 12 likely benign, 6 pathogenic, 4 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1188124	NM_001243133.2(NLRP3):c.2575T>C (p.Tyr859His)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1701129	NM_001243133.2(NLRP3):c.778_780delinsTGG (p.Arg260Trp)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4370	NM_001243133.2(NLRP3):c.1316C>T (p.Ala439Val)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4376	NM_001243133.2(NLRP3):c.1718T>C (p.Phe573Ser)	NLRP3	Pathogenic	no assertion criteria provided
4377	NM_001243133.2(NLRP3):c.907G>A (p.Asp303Asn)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
4378	NM_001243133.2(NLRP3):c.926T>C (p.Phe309Ser)	NLRP3	Pathogenic	no assertion criteria provided
4379	NM_001243133.2(NLRP3):c.1058T>C (p.Leu353Pro)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
97909	NM_001243133.2(NLRP3):c.1043C>T (p.Thr348Met)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
97960	NM_001243133.2(NLRP3):c.2576A>G (p.Tyr859Cys)	NLRP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97987	NM_001243133.2(NLRP3):c.931G>A (p.Glu311Lys)	NLRP3	Pathogenic	criteria provided, multiple submitters, no conflicts
97912	NM_001243133.2(NLRP3):c.1054G>A (p.Ala352Thr)	NLRP3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
97958	NM_001243133.2(NLRP3):c.2263G>C (p.Gly755Arg)	NLRP3	Likely pathogenic	no assertion criteria provided
1028307	NM_001243133.2(NLRP3):c.1937A>G (p.Asp646Gly)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058144	NM_001243133.2(NLRP3):c.1371G>T (p.Glu457Asp)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138532	NM_001243133.2(NLRP3):c.1584C>T (p.Ala528=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
138534	NM_001243133.2(NLRP3):c.2118C>T (p.Leu706=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1446237	NM_001243133.2(NLRP3):c.2273T>C (p.Val758Ala)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1548717	NM_001243133.2(NLRP3):c.1650G>A (p.Lys550=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1980828	NM_001243133.2(NLRP3):c.800A>G (p.Gln267Arg)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234288	NM_001243133.2(NLRP3):c.404G>A (p.Arg135His)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234290	NM_001243133.2(NLRP3):c.2176A>G (p.Ser726Gly)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234291	NM_001243133.2(NLRP3):c.2425G>A (p.Gly809Ser)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234300	NM_001243133.2(NLRP3):c.1064A>G (p.Lys355Arg)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234304	NM_001243133.2(NLRP3):c.2611G>A (p.Ala871Thr)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234305	NM_001243133.2(NLRP3):c.2738C>T (p.Thr913Met)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234451	NM_001243133.2(NLRP3):c.2761A>G (p.Thr921Ala)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245593	NM_001243133.2(NLRP3):c.208G>A (p.Val70Met)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
259561	NM_001243133.2(NLRP3):c.2107C>A (p.Gln703Lys)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296934	NM_001243133.2(NLRP3):c.-122T>C	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
296938	NM_001243133.2(NLRP3):c.28A>C (p.Arg10=)	NLRP3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
NLRP3	Definitive	Autosomal dominant	CINCA syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NLRP3	Orphanet:1451	CINCA syndrome
NLRP3	Orphanet:47045	Familial cold urticaria
NLRP3	Orphanet:575	Muckle-Wells syndrome
NLRP3	Orphanet:647815	Keratitis fugax hereditaria

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
NLRP3	HGNC:16400	ENSG00000162711	Q96P20	NACHT, LRR and PYD domains-containing protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NLRP3	NACHT, LRR and PYD domains-containing protein 3	Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NLRP3	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase

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
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NLRP3	172	broad	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NLRP3	3,797

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NLRP3	Q96P20	24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
The NLRP3 inflammasome	1	671.8×	0.005	NLRP3
Purinergic signaling in leishmaniasis infection	1	423.0×	0.005	NLRP3
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	356.9×	0.005	NLRP3
Metalloprotease DUBs	1	300.5×	0.005	NLRP3
SARS-CoV-1 activates/modulates innate immune responses	1	271.9×	0.005	NLRP3
Cytoprotection by HMOX1	1	184.2×	0.006	NLRP3
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	89.2×	0.011	NLRP3

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
detection of biotic stimulus	1	4213.0×	0.003	NLRP3
negative regulation of acute inflammatory response	1	2407.4×	0.003	NLRP3
positive regulation of type 2 immune response	1	2407.4×	0.003	NLRP3
NLRP3 inflammasome complex assembly	1	2407.4×	0.003	NLRP3
positive regulation of T-helper 2 cell differentiation	1	2106.5×	0.003	NLRP3
osmosensory signaling pathway	1	1532.0×	0.003	NLRP3
positive regulation of T-helper 2 cell cytokine production	1	1532.0×	0.003	NLRP3
pattern recognition receptor signaling pathway	1	991.3×	0.004	NLRP3
positive regulation of interleukin-4 production	1	561.7×	0.005	NLRP3
negative regulation of interleukin-1 beta production	1	510.7×	0.005	NLRP3
pyroptotic inflammatory response	1	510.7×	0.005	NLRP3
negative regulation of non-canonical NF-kappaB signal transduction	1	510.7×	0.005	NLRP3
positive regulation of interleukin-1 beta production	1	259.3×	0.008	NLRP3
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.008	NLRP3
defense response	1	216.1×	0.008	NLRP3
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.008	NLRP3
cellular response to virus	1	200.6×	0.008	NLRP3
regulation of inflammatory response	1	168.5×	0.009	NLRP3
protein maturation	1	163.6×	0.009	NLRP3
positive regulation of inflammatory response	1	145.3×	0.010	NLRP3
negative regulation of inflammatory response	1	137.0×	0.010	NLRP3
protein homooligomerization	1	122.1×	0.010	NLRP3
cellular response to lipopolysaccharide	1	98.0×	0.012	NLRP3
inflammatory response	1	37.7×	0.031	NLRP3
innate immune response	1	33.6×	0.033	NLRP3
apoptotic process	1	28.7×	0.038	NLRP3
signal transduction	1	16.1×	0.065	NLRP3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	NLRP3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) 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
NLRP3	CLOMIPHENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NLRP3	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
CURCUMIN	3	NLRP3
JT-001	3	NLRP3
TRICLOCARBAN	2	NLRP3
CLIOXANIDE	2	NLRP3
DAPANSUTRILE	2	NLRP3
USNOFLAST	2	NLRP3
INZOMELID	1	NLRP3
BMS-986299	1	NLRP3
NT-0796	1	NLRP3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NLRP3	534	Binding:527, Functional:6, ADMET:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NLRP3	534

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

11 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)
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
CURCUMIN	3	NLRP3
JT-001	3	NLRP3
TRICLOCARBAN	2	NLRP3
CLIOXANIDE	2	NLRP3
DAPANSUTRILE	2	NLRP3
USNOFLAST	2	NLRP3
INZOMELID	1	NLRP3
BMS-986299	1	NLRP3
NT-0796	1	NLRP3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NLRP3
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: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	5
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00685373	PHASE3	COMPLETED	Efficacy and Safety of ACZ885 in Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
NCT00770601	PHASE3	TERMINATED	Canakinumab to Treat Neonatal-Onset Multisystem Inflammatory Disease
NCT00991146	PHASE3	COMPLETED	Efficacy and Safety Study of Canakinumab Administered for 6 Months (24 Weeks) in Japanese Patients With Cryopyrin-associated Periodic Syndromes Followed by an Extension Phase
NCT01302860	PHASE3	COMPLETED	Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
NCT01576367	PHASE3	COMPLETED	Efficacy, Safety and Tolerability of ACZ885 in Pediatric Patients With the Following Cryopyrin-associated Periodic Syndromes: Familial Cold Autoinflammatory Syndrome, Muckle-Wells Syndrome, or Neonatal Onset Multisystem Inflammatory Disease
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)
NCT06544018	Not specified	RECRUITING	Circadian Rhythm Deregulation in Patients With CAPS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CANAKINUMAB	4	5