Muckle-Wells Syndrome

Mendelian MONDO:0008633 Pathograph 20 Show in embeddings browser Autoinflammatory diseases Cryopyrin-associated periodic syndromes

Muckle-Wells syndrome (MWS) is a dominantly inherited autoinflammatory disorder representing the intermediate-severity phenotype of the cryopyrin-associated periodic syndrome (CAPS) spectrum, sitting between the mild familial cold autoinflammatory syndrome (FCAS) and the severe CINCA/NOMID. It is caused by heterozygous gain-of-function mutations in NLRP3 (CIAS1, encoding cryopyrin) that lower the activation threshold of the NLRP3 inflammasome, producing constitutive caspase-1 activation and excessive interleukin-1beta (IL-1beta) secretion. Clinically it is characterized by recurrent (largely non-cold-triggered) episodes of urticaria-like rash, fever, arthralgia, myalgia, conjunctivitis, and fatigue, together with progressive sensorineural hearing loss from cochlear autoinflammation. Its most serious long-term complication is AA (serum amyloid A) amyloidosis with renal involvement, driven by sustained systemic inflammation. IL-1 blockade (anakinra, canakinumab, rilonacept) is the defining, disease-modifying therapy.

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2
Mappings
1
Inheritance
6
Pathophys.
10
Phenotypes
1
Hypotheses
20
Pathograph
1
Genes
4
Medical Actions
2
Differentials
3
References
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
IUIS Category
autoinflammatory syndrome
🔗

Mappings

MONDO
MONDO:0008633 Muckle-Wells syndrome
skos:exactMatch MONDO
Primary MONDO identifier for Muckle-Wells syndrome (matches disease_term).
NCIT
NCIT:C84657 Cryopyrin-Associated Periodic Syndrome
skos:broadMatch NCIT
NCIT has no MWS-specific term; MWS is the intermediate phenotype of the CAPS spectrum captured by this parent concept.
NCIT
NCIT:C84657 Cryopyrin-Associated Periodic Syndrome
skos:broadMatch NCIT
NCIT has no MWS-specific term; MWS is the intermediate phenotype of the CAPS spectrum captured by this parent concept.
👪

Inheritance

1
Autosomal dominant HP:0000006
Muckle-Wells syndrome follows autosomal dominant inheritance, caused by heterozygous gain-of-function NLRP3 variants.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:11687797 SUPPORT Human Clinical
"Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present."
Original description establishing MWS as an autosomal-dominant periodic fever syndrome.
◈

Mechanistic Hypotheses

1
Canonical NLRP3 Inflammasome / IL-1beta Model
canonical_nlrp3_il1_inflammasome_model CANONICAL
Gain-of-function NLRP3 mutations cause constitutive inflammasome assembly and caspase-1 activation, driving excessive IL-1beta production as the central effector of the systemic and organ-specific inflammation of MWS. The dominant pathogenic role of IL-1beta is established by the rapid clinical and biochemical response to IL-1 blockade.
⚙

Pathophysiology

6
NLRP3 gain-of-function activation
Heterozygous gain-of-function missense mutations in NLRP3 (CIAS1, encoding cryopyrin) lower the activation threshold of the NLRP3 inflammasome. NLRP3 is an intracellular NOD-like receptor sensor with a pyrin domain, a NACHT nucleotide-binding domain, and a leucine-rich repeat region; MWS mutations drive the sensor outside its normal autoinhibitory regulatory constraints.
Monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology. Macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
NLRP3 hgnc:16400 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NLRP3 (hgnc:16400). hgnc:16400 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context NLRP3 hgnc:16400 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns NLRP3 (hgnc:16400). hgnc:16400 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Downstream
Constitutive NLRP3 inflammasome activation
Show evidence (2 references)
PMID:11687797 SUPPORT Human Clinical
"This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region, suggesting a role in the regulation of inflammation and apoptosis."
Identification of the NLRP3/CIAS1 domain architecture, whose gain-of-function mutation causes the CAPS spectrum including Muckle-Wells syndrome.
PMID:33401496 SUPPORT Other
"The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β."
Establishes heterozygous NLRP3 gain-of-function variants driving inflammasome activation and IL-1beta overproduction across the CAPS spectrum, which includes MWS as the intermediate phenotype.
Constitutive NLRP3 inflammasome activation
Mutant cryopyrin assembles the NLRP3 inflammasome complex (NLRP3, ASC/PYCARD, pro-caspase-1) with a reduced requirement for a second activating signal. This constitutive assembly in myeloid cells continuously activates caspase-1.
Monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
NLRP3 inflammasome complex assembly GO:0044546 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased NLRP3 inflammasome complex assembly (GO:0044546). GO:0044546 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Caspase-1 activation and IL-1beta overproduction
Show evidence (1 reference)
PMID:38146057 SUPPORT Other
"NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18."
Establishes inflammasome assembly as the central event linking NLRP3 to downstream IL-1/IL-18-mediated inflammation.
Caspase-1 activation and IL-1beta overproduction
The assembled NLRP3 inflammasome activates caspase-1, which cleaves pro-IL-1beta and pro-IL-18 into their mature secreted forms and triggers gasdermin-D-dependent pyroptosis. Excess IL-1beta is the principal driver of the systemic autoinflammatory phenotype of MWS.
Interleukin-1 beta production GO:0032611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Interleukin-1 beta production (GO:0032611). GO:0032611 is a biological process from the Gene Ontology. ↑ INCREASED Pyroptotic inflammatory response GO:0070269 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Pyroptotic inflammatory response (GO:0070269). GO:0070269 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Systemic autoinflammation
Show evidence (2 references)
PMID:32983099 SUPPORT Other
"recruit and activate caspase-1, which cleaves the proinflammatory cytokines pro-IL-1β, pro-IL-18, and gasdermin-D (GSDMD)"
Establishes that the activated inflammasome recruits caspase-1 to cleave pro-IL-1beta, pro-IL-18, and gasdermin-D, the molecular basis of this node.
PMID:39334417 SUPPORT Human Clinical
"Cryopyrin-associated periodic syndrome (CAPS) is characterized by excessive IL-1β release resulting in systemic and organ inflammation."
Confirms excessive IL-1beta release as the proximate cause of systemic and organ inflammation in CAPS, including MWS.
Systemic autoinflammation
The convergent systemic phenotype of MWS: recurrent, largely non-cold-triggered episodes of sterile systemic inflammation driven by IL-1beta. Clinically it manifests as urticaria-like rash, fever, arthralgia, myalgia, conjunctivitis, and fatigue, with elevated acute-phase reactants (CRP, serum amyloid A).
Inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Urticarial rash IL-1-driven systemic inflammation produces the recurrent urticaria-like rash.
Recurrent fever IL-1-driven systemic inflammation produces recurrent fever episodes.
Arthralgia Systemic inflammation produces episodic joint pain.
Conjunctivitis Ocular surface inflammation produces conjunctivitis.
Myalgia IL-1-driven systemic inflammation produces myalgia during inflammatory episodes.
Fatigue Chronic systemic inflammation produces fatigue and malaise.
Elevated C-reactive protein Systemic IL-1-driven inflammation elevates acute-phase reactants including C-reactive protein.
Cochlear autoinflammation and hearing loss Systemic NLRP3/IL-1 autoinflammation extends to the cochlea, producing progressive sensorineural hearing loss.
AA (serum amyloid A) amyloidosis Sustained systemic inflammation drives chronic serum amyloid A elevation and AA amyloid deposition.
Show evidence (1 reference)
PMID:33401496 SUPPORT Other
"Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic."
Characterizes the multi-domain (dermatologic, musculoskeletal, ocular, otologic) chronic systemic inflammatory phenotype shared across CAPS, of which MWS is the intermediate form.
Cochlear autoinflammation and hearing loss
Progressive sensorineural hearing loss in MWS reflects local NLRP3 inflammasome-driven autoinflammation in the cochlea. Resident macrophage/monocyte-like cells in the cochlea activate the NLRP3 inflammasome and secrete IL-1beta, producing chronic cochlear inflammation and progressive hearing loss.
Macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
Inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Cochlea UBERON:0001844 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Cochlea (UBERON:0001844). UBERON:0001844 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sensorineural hearing loss Cochlear autoinflammation produces progressive sensorineural hearing loss.
Show evidence (1 reference)
PMID:32194497 SUPPORT Model Organism
"The inflammasome can indeed be activated in macrophage/monocyte-like cells of the mouse cochlea, with secretion of IL-1β."
Mouse cochlear evidence that macrophage/monocyte-like cells activate the inflammasome and secrete IL-1beta, the cellular basis of cochlear autoinflammation.
AA (serum amyloid A) amyloidosis
The most serious long-term complication of MWS. Sustained systemic inflammation keeps the acute-phase precursor serum amyloid A (SAA) chronically elevated; SAA misfolds and aggregates into insoluble AA amyloid fibrils that deposit in the extracellular space, preferentially in the kidney, causing proteinuria and progressive renal amyloidosis. This node substitutes serum amyloid A as the amyloidogenic precursor of the conserved amyloidogenesis chain.
Amyloid fibril formation GO:1990000 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Amyloid fibril formation (GO:1990000). GO:1990000 is a biological process from the Gene Ontology. ↑ INCREASED
Kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Renal amyloidosis AA amyloid deposition in the kidney produces renal amyloidosis with proteinuria.
Proteinuria Glomerular AA amyloid deposition produces proteinuria.
Show evidence (1 reference)
PMID:36275641 SUPPORT Other
"progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
Names progressive sensorineural hearing loss and SAA-driven renal (AA) amyloidosis as the most specific findings of Muckle-Wells syndrome, grounding serum amyloid A as the amyloidogenic precursor.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Muckle-Wells Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Cardiovascular 2
Urticarial rash HP:0001025 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Urticaria (HP:0001025), qualified as temporality recurrent. HP:0001025 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:32983099 SUPPORT Other
"neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
Inflammasome review listing neutrophilic urticaria among the cardinal CAPS clinical features, of which MWS is the intermediate phenotype.
Conjunctivitis HP:0000509 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conjunctivitis (HP:0000509). HP:0000509 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32983099 SUPPORT Other
"neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
Conjunctivitis is a cardinal CAPS/MWS inflammatory feature.
Ear 1
Sensorineural hearing loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407), qualified as course progressive. HP:0000407 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:11687797 SUPPORT Human Clinical
"Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present."
Original description of MWS defining it as an autosomal-dominant periodic fever syndrome with frequent sensorineural hearing loss and, unlike FCAS, symptoms not precipitated by cold.
PMID:36275641 SUPPORT Other
"progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
Names progressive sensorineural hearing loss as one of the most specific findings of Muckle-Wells syndrome.
Genitourinary 2
Renal amyloidosis HP:0001917 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal amyloidosis (HP:0001917). HP:0001917 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36275641 SUPPORT Other
"progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
Renal (AA) amyloidosis driven by sustained SAA elevation is a specific and serious long-term complication of Muckle-Wells syndrome.
Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36275641 SUPPORT Other
"progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
Renal AA amyloidosis in MWS characteristically presents with proteinuria; the cited review documents the renal amyloidosis association, with proteinuria as its expected renal readout (the snippet supports the renal amyloidosis association rather than naming proteinuria explicitly).
Metabolism 2
Recurrent fever HP:0001954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever (HP:0001954). HP:0001954 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32983099 SUPPORT Other
"neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
Fever is a cardinal CAPS/MWS inflammatory feature.
Elevated C-reactive protein Elevated circulating C-reactive protein concentration HP:0011227 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating C-reactive protein concentration (HP:0011227). HP:0011227 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32983099 SUPPORT Other
"While all patients present with ESR and CRP elevation, different from CAPS flare"
Reports that patients across these inflammasome diseases, including CAPS flares, present with elevated ESR and CRP, supporting elevated C-reactive protein as a laboratory feature of MWS.
Constitutional 3
Arthralgia HP:0002829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthralgia (HP:0002829). HP:0002829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32983099 SUPPORT Other
"neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
Arthralgia is a cardinal CAPS/MWS inflammatory feature.
Myalgia HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39334417 SUPPORT Human Clinical
"rash, arthralgia, myalgia, headache or migraine, conjunctivitis, fatigue or malaise"
Myalgia is one of the core inflammatory symptoms captured in the CAPS disease-activity global assessment.
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39334417 SUPPORT Human Clinical
"rash, arthralgia, myalgia, headache or migraine, conjunctivitis, fatigue or malaise"
Fatigue/malaise is one of the core inflammatory symptoms captured in the CAPS disease-activity global assessment.
🧬

Genetic Associations

1
NLRP3 (Causative)
Gene: NLRP3 hgnc:16400 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NLRP3 (hgnc:16400). hgnc:16400 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal dominant
Show evidence (1 reference)
PMID:11687797 SUPPORT Human Clinical
"This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS."
Original identification of NLRP3/CIAS1 mutations segregating with disease in FCAS and MWS families, establishing NLRP3 as the causative gene.
💊

Medical Actions

4
Anakinra
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anakinra CHEBI:231683 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses anakinra (CHEBI:231683). CHEBI:231683 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Other
Recombinant IL-1 receptor antagonist (blocks IL-1alpha and IL-1beta), given daily; effective across the CAPS spectrum including MWS, rapidly controlling inflammation and normalizing acute-phase reactants.
Mechanism Target:
INHIBITS Caspase-1 activation and IL-1beta overproduction — Anakinra competitively blocks the IL-1 receptor, neutralizing the excess IL-1beta signaling produced by the constitutively active inflammasome.
Show evidence (1 reference)
PMID:32983099 SUPPORT Other
"IL-1 blockade with anakinra, canakinumab, and rilonacept is standard of care in CAPS with a well-established safety profile."
Establishes anakinra (IL-1 receptor antagonist) as a standard-of-care IL-1 blockade agent for CAPS, including MWS.
Canakinumab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Canakinumab NCIT:C80971 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Canakinumab (NCIT:C80971). NCIT:C80971 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anti-IL-1beta monoclonal antibody administered every 4-8 weeks; approved for CAPS. Reduces flares and normalizes CRP/SAA, and is the prototypical long-acting IL-1 blockade for MWS.
Mechanism Target:
INHIBITS Caspase-1 activation and IL-1beta overproduction — Canakinumab binds and neutralizes IL-1beta, the principal effector cytokine of the constitutively active NLRP3 inflammasome.
Show evidence (2 references)
PMID:39334417 SUPPORT Human Clinical
"After treatments, 60% (6/10) of CAPS patients achieved complete remission without relapse and the rest showed minimal disease activity."
Real-world CAPS cohort showing canakinumab induces remission or minimal disease activity, supporting its efficacy for MWS.
PMID:32983099 SUPPORT Other
"IL-1 blockade with anakinra, canakinumab, and rilonacept is standard of care in CAPS with a well-established safety profile."
Establishes canakinumab (anti-IL-1beta monoclonal antibody) as a standard-of-care IL-1 blockade agent for CAPS, including MWS.
Rilonacept
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Rilonacept NCIT:C84137 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Rilonacept (NCIT:C84137). NCIT:C84137 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
IL-1 trap (soluble decoy receptor capturing IL-1alpha and IL-1beta) administered weekly; reduces flares in the FCAS/MWS end of the CAPS spectrum.
Mechanism Target:
INHIBITS Caspase-1 activation and IL-1beta overproduction — Rilonacept acts as a soluble decoy receptor that sequesters IL-1beta (and IL-1alpha), blocking downstream IL-1 signaling from the inflammasome.
Show evidence (1 reference)
PMID:32983099 SUPPORT Other
"IL-1 blockade with anakinra, canakinumab, and rilonacept is standard of care in CAPS with a well-established safety profile."
Establishes rilonacept (IL-1 trap) as a standard-of-care IL-1 blockade agent for CAPS, including MWS.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal dominant inheritance warrants genetic counseling for affected MWS families.
Show evidence (1 reference)
PMID:11687797 SUPPORT Human Clinical
"This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS."
Autosomal dominant segregation of NLRP3 mutations in MWS families supports genetic counseling.
🔬

Biochemical Markers

2
Serum amyloid A (ELEVATED)
Show evidence (1 reference)
PMID:36275641 SUPPORT Other
"progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
Reports sustained elevation (increase) of serum amyloid A protein as a specific feature of Muckle-Wells syndrome and the precursor for renal AA amyloidosis.
C-reactive protein (ELEVATED)
Show evidence (1 reference)
PMID:32983099 SUPPORT Other
"While all patients present with ESR and CRP elevation, different from CAPS flare"
Reports elevated ESR and CRP across these inflammasome diseases including CAPS flares, supporting elevated CRP as a biochemical marker of MWS disease activity.
📊

Prevalence

1
Worldwide
Point Prevalence 0.41 per 100,000 (0.27–0.55) 1–9 per 1,000,000
CAPS-spectrum estimate (2.7-5.5 per 1,000,000); MWS is the intermediate phenotype within CAPS and is not tabulated separately. The true prevalence is likely underestimated because CAPS is often misdiagnosed.
Show evidence (1 reference)
PMID:36275641 SUPPORT Other
"ranging from 2.7 to 5.5 per 1 million and might be higher"
Reports the CAPS-spectrum prevalence range (2.7-5.5 per million), placing MWS in the ultra-rare 1-9 per 1,000,000 band.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Muckle-Wells Syndrome:

Familial cold autoinflammatory syndrome MONDO:0018768
Overlapping Features The mildest CAPS phenotype, with cold-triggered urticarial episodes, fever, and arthralgia and, unlike MWS, generally without progressive hearing loss or amyloidosis.
Show evidence (1 reference)
PMID:11687797 SUPPORT Human Clinical
"Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
FCAS is the milder, cold-triggered CAPS phenotype distinguished from MWS, which is largely cold-independent and carries hearing loss and amyloidosis risk.
CINCA syndrome MONDO:0011776
Overlapping Features The most severe CAPS phenotype (NOMID), with neonatal-onset chronic aseptic meningitis, deforming arthropathy with epiphyseal overgrowth, and neurodevelopmental impairment absent in MWS.
Show evidence (1 reference)
PMID:36275641 SUPPORT Other
"higher levels of acute phase reactants and severe articular and neurological involvement"
CINCA/NOMID is distinguished from MWS by its severe articular and neurological (CNS) involvement and higher acute-phase reactants, features absent in the intermediate MWS phenotype.
{ }

Source YAML

click to show 
name: Muckle-Wells Syndrome
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
synonyms:
- MWS
- Urticaria-deafness-amyloidosis syndrome
- UDA syndrome
- NLRP3-associated autoinflammatory disease, intermediate
disease_term:
  preferred_term: Muckle-Wells syndrome
  term:
    id: MONDO:0008633
    label: Muckle-Wells syndrome
parents:
- Autoinflammatory diseases
- Cryopyrin-associated periodic syndromes
description: >
  Muckle-Wells syndrome (MWS) is a dominantly inherited autoinflammatory
  disorder representing the intermediate-severity phenotype of the
  cryopyrin-associated periodic syndrome (CAPS) spectrum, sitting between the
  mild familial cold autoinflammatory syndrome (FCAS) and the severe
  CINCA/NOMID. It is caused by heterozygous gain-of-function mutations in NLRP3
  (CIAS1, encoding cryopyrin) that lower the activation threshold of the NLRP3
  inflammasome, producing constitutive caspase-1 activation and excessive
  interleukin-1beta (IL-1beta) secretion. Clinically it is characterized by
  recurrent (largely non-cold-triggered) episodes of urticaria-like rash,
  fever, arthralgia, myalgia, conjunctivitis, and fatigue, together with
  progressive sensorineural hearing loss from cochlear autoinflammation. Its
  most serious long-term complication is AA (serum amyloid A) amyloidosis with
  renal involvement, driven by sustained systemic inflammation. IL-1 blockade
  (anakinra, canakinumab, rilonacept) is the defining, disease-modifying
  therapy.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  iuis_category:
    classification_value: autoinflammatory syndrome
references:
- reference: PMID:11687797
  title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
- reference: PMID:33401496
  title: "Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?"
- reference: PMID:36275641
  title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
pathophysiology:
- name: NLRP3 gain-of-function activation
  biological_scale: MOLECULAR
  description: >
    Heterozygous gain-of-function missense mutations in NLRP3 (CIAS1, encoding
    cryopyrin) lower the activation threshold of the NLRP3 inflammasome. NLRP3
    is an intracellular NOD-like receptor sensor with a pyrin domain, a NACHT
    nucleotide-binding domain, and a leucine-rich repeat region; MWS mutations
    drive the sensor outside its normal autoinhibitory regulatory constraints.
  gene:
    preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  genetic_context:
    gene:
      preferred_term: NLRP3
      term:
        id: hgnc:16400
        label: NLRP3
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
  cell_types:
  - preferred_term: Monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  downstream:
  - target: Constitutive NLRP3 inflammasome activation
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region, suggesting a role in the regulation of inflammation and apoptosis."
    explanation: Identification of the NLRP3/CIAS1 domain architecture, whose gain-of-function mutation causes the CAPS spectrum including Muckle-Wells syndrome.
  - reference: PMID:33401496
    reference_title: "Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β."
    explanation: Establishes heterozygous NLRP3 gain-of-function variants driving inflammasome activation and IL-1beta overproduction across the CAPS spectrum, which includes MWS as the intermediate phenotype.
- name: Constitutive NLRP3 inflammasome activation
  biological_scale: CELLULAR
  description: >
    Mutant cryopyrin assembles the NLRP3 inflammasome complex (NLRP3, ASC/PYCARD,
    pro-caspase-1) with a reduced requirement for a second activating signal.
    This constitutive assembly in myeloid cells continuously activates caspase-1.
  cell_types:
  - preferred_term: Monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
    modifier: INCREASED
  downstream:
  - target: Caspase-1 activation and IL-1beta overproduction
  evidence:
  - reference: PMID:38146057
    reference_title: "The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18."
    explanation: Establishes inflammasome assembly as the central event linking NLRP3 to downstream IL-1/IL-18-mediated inflammation.
- name: Caspase-1 activation and IL-1beta overproduction
  biological_scale: MOLECULAR
  description: >
    The assembled NLRP3 inflammasome activates caspase-1, which cleaves
    pro-IL-1beta and pro-IL-18 into their mature secreted forms and triggers
    gasdermin-D-dependent pyroptosis. Excess IL-1beta is the principal driver of
    the systemic autoinflammatory phenotype of MWS.
  biological_processes:
  - preferred_term: Interleukin-1 beta production
    term:
      id: GO:0032611
      label: interleukin-1 beta production
    modifier: INCREASED
  - preferred_term: Pyroptotic inflammatory response
    term:
      id: GO:0070269
      label: pyroptotic inflammatory response
    modifier: INCREASED
  downstream:
  - target: Systemic autoinflammation
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "recruit and activate caspase-1, which cleaves the proinflammatory cytokines pro-IL-1β, pro-IL-18, and gasdermin-D (GSDMD)"
    explanation: Establishes that the activated inflammasome recruits caspase-1 to cleave pro-IL-1beta, pro-IL-18, and gasdermin-D, the molecular basis of this node.
  - reference: PMID:39334417
    reference_title: "Effectiveness and safety of canakinumab in cryopyrin-associated periodic syndrome: a retrospective study in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cryopyrin-associated periodic syndrome (CAPS) is characterized by excessive IL-1β release resulting in systemic and organ inflammation."
    explanation: Confirms excessive IL-1beta release as the proximate cause of systemic and organ inflammation in CAPS, including MWS.
- name: Systemic autoinflammation
  biological_scale: ORGANISM
  description: >
    The convergent systemic phenotype of MWS: recurrent, largely
    non-cold-triggered episodes of sterile systemic inflammation driven by
    IL-1beta. Clinically it manifests as urticaria-like rash, fever, arthralgia,
    myalgia, conjunctivitis, and fatigue, with elevated acute-phase reactants
    (CRP, serum amyloid A).
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Urticarial rash
    causal_link_type: DIRECT
    description: IL-1-driven systemic inflammation produces the recurrent urticaria-like rash.
  - target: Recurrent fever
    causal_link_type: DIRECT
    description: IL-1-driven systemic inflammation produces recurrent fever episodes.
  - target: Arthralgia
    causal_link_type: DIRECT
    description: Systemic inflammation produces episodic joint pain.
  - target: Conjunctivitis
    causal_link_type: DIRECT
    description: Ocular surface inflammation produces conjunctivitis.
  - target: Myalgia
    causal_link_type: DIRECT
    description: IL-1-driven systemic inflammation produces myalgia during inflammatory episodes.
  - target: Fatigue
    causal_link_type: DIRECT
    description: Chronic systemic inflammation produces fatigue and malaise.
  - target: Elevated C-reactive protein
    causal_link_type: DIRECT
    description: Systemic IL-1-driven inflammation elevates acute-phase reactants including C-reactive protein.
  - target: Cochlear autoinflammation and hearing loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Systemic NLRP3/IL-1 autoinflammation extends to the cochlea, producing progressive sensorineural hearing loss.
  - target: AA (serum amyloid A) amyloidosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Sustained systemic inflammation drives chronic serum amyloid A elevation and AA amyloid deposition.
  evidence:
  - reference: PMID:33401496
    reference_title: "Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic."
    explanation: Characterizes the multi-domain (dermatologic, musculoskeletal, ocular, otologic) chronic systemic inflammatory phenotype shared across CAPS, of which MWS is the intermediate form.
- name: Cochlear autoinflammation and hearing loss
  biological_scale: TISSUE
  description: >
    Progressive sensorineural hearing loss in MWS reflects local NLRP3
    inflammasome-driven autoinflammation in the cochlea. Resident
    macrophage/monocyte-like cells in the cochlea activate the NLRP3
    inflammasome and secrete IL-1beta, producing chronic cochlear inflammation
    and progressive hearing loss.
  locations:
  - preferred_term: Cochlea
    term:
      id: UBERON:0001844
      label: cochlea
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  downstream:
  - target: Sensorineural hearing loss
    causal_link_type: DIRECT
    description: Cochlear autoinflammation produces progressive sensorineural hearing loss.
  evidence:
  - reference: PMID:32194497
    reference_title: "Genetic Hearing Loss Associated With Autoinflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The inflammasome can indeed be activated in macrophage/monocyte-like cells of the mouse cochlea, with secretion of IL-1β."
    explanation: Mouse cochlear evidence that macrophage/monocyte-like cells activate the inflammasome and secrete IL-1beta, the cellular basis of cochlear autoinflammation.
- name: AA (serum amyloid A) amyloidosis
  biological_scale: TISSUE
  conforms_to: "amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition"
  description: >
    The most serious long-term complication of MWS. Sustained systemic
    inflammation keeps the acute-phase precursor serum amyloid A (SAA)
    chronically elevated; SAA misfolds and aggregates into insoluble AA amyloid
    fibrils that deposit in the extracellular space, preferentially in the
    kidney, causing proteinuria and progressive renal amyloidosis. This node
    substitutes serum amyloid A as the amyloidogenic precursor of the conserved
    amyloidogenesis chain.
  locations:
  - preferred_term: Kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: Amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  downstream:
  - target: Renal amyloidosis
    causal_link_type: DIRECT
    description: AA amyloid deposition in the kidney produces renal amyloidosis with proteinuria.
  - target: Proteinuria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Glomerular AA amyloid deposition produces proteinuria.
  evidence:
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
    explanation: Names progressive sensorineural hearing loss and SAA-driven renal (AA) amyloidosis as the most specific findings of Muckle-Wells syndrome, grounding serum amyloid A as the amyloidogenic precursor.
phenotypes:
- name: Urticarial rash
  description: >
    Recurrent urticaria-like (neutrophilic) skin rash, a cardinal cutaneous
    manifestation of MWS. Unlike FCAS, episodes are largely not precipitated by
    generalized cold exposure.
  phenotype_term:
    preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
    temporality: RECURRENT
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
    explanation: Inflammasome review listing neutrophilic urticaria among the cardinal CAPS clinical features, of which MWS is the intermediate phenotype.
- name: Recurrent fever
  description: Recurrent episodic fever accompanying inflammatory attacks, typically lasting 1-3 days.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
    explanation: Fever is a cardinal CAPS/MWS inflammatory feature.
- name: Arthralgia
  description: Joint pain during inflammatory episodes.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
    explanation: Arthralgia is a cardinal CAPS/MWS inflammatory feature.
- name: Conjunctivitis
  description: Ocular surface inflammation (conjunctivitis) during flares.
  phenotype_term:
    preferred_term: Conjunctivitis
    term:
      id: HP:0000509
      label: Conjunctivitis
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
    explanation: Conjunctivitis is a cardinal CAPS/MWS inflammatory feature.
- name: Myalgia
  description: Muscle pain during cold-independent inflammatory episodes.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:39334417
    reference_title: "Effectiveness and safety of canakinumab in cryopyrin-associated periodic syndrome: a retrospective study in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rash, arthralgia, myalgia, headache or migraine, conjunctivitis, fatigue or malaise"
    explanation: Myalgia is one of the core inflammatory symptoms captured in the CAPS disease-activity global assessment.
- name: Fatigue
  description: Fatigue and malaise accompanying systemic inflammation.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:39334417
    reference_title: "Effectiveness and safety of canakinumab in cryopyrin-associated periodic syndrome: a retrospective study in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rash, arthralgia, myalgia, headache or migraine, conjunctivitis, fatigue or malaise"
    explanation: Fatigue/malaise is one of the core inflammatory symptoms captured in the CAPS disease-activity global assessment.
- name: Sensorineural hearing loss
  description: >
    Progressive sensorineural hearing loss is a hallmark of MWS, more prominent
    than in mild FCAS, driven by chronic cochlear autoinflammation.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present."
    explanation: Original description of MWS defining it as an autosomal-dominant periodic fever syndrome with frequent sensorineural hearing loss and, unlike FCAS, symptoms not precipitated by cold.
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
    explanation: Names progressive sensorineural hearing loss as one of the most specific findings of Muckle-Wells syndrome.
- name: Renal amyloidosis
  description: >
    AA (secondary) amyloidosis with renal involvement, producing proteinuria and
    progressive renal impairment, is the most serious long-term complication of
    MWS, driven by sustained serum amyloid A elevation.
  phenotype_term:
    preferred_term: Renal amyloidosis
    term:
      id: HP:0001917
      label: Renal amyloidosis
  evidence:
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
    explanation: Renal (AA) amyloidosis driven by sustained SAA elevation is a specific and serious long-term complication of Muckle-Wells syndrome.
- name: Proteinuria
  description: >
    Proteinuria is the typical renal manifestation of AA amyloid deposition in
    the glomeruli in MWS.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
    explanation: Renal AA amyloidosis in MWS characteristically presents with proteinuria; the cited review documents the renal amyloidosis association, with proteinuria as its expected renal readout (the snippet supports the renal amyloidosis association rather than naming proteinuria explicitly).
- name: Elevated C-reactive protein
  category: Laboratory
  description: >
    Elevated acute-phase reactants (CRP and serum amyloid A) accompany
    inflammatory attacks and are used for diagnosis and treat-to-target
    monitoring.
  phenotype_term:
    preferred_term: Elevated circulating C-reactive protein concentration
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While all patients present with ESR and CRP elevation, different from CAPS flare"
    explanation: Reports that patients across these inflammasome diseases, including CAPS flares, present with elevated ESR and CRP, supporting elevated C-reactive protein as a laboratory feature of MWS.
biochemical:
- name: Serum amyloid A
  presence: ELEVATED
  notes: >
    Acute-phase reactant; sustained elevation is the precursor for AA amyloid
    deposition, making SAA normalization a treat-to-target goal in MWS.
  evidence:
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"
    explanation: Reports sustained elevation (increase) of serum amyloid A protein as a specific feature of Muckle-Wells syndrome and the precursor for renal AA amyloidosis.
- name: C-reactive protein
  presence: ELEVATED
  notes: >
    Acute-phase reactant elevated during inflammatory attacks; used with serum
    amyloid A to assess MWS disease activity and treatment response.
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While all patients present with ESR and CRP elevation, different from CAPS flare"
    explanation: Reports elevated ESR and CRP across these inflammasome diseases including CAPS flares, supporting elevated CRP as a biochemical marker of MWS disease activity.
genetic:
- name: NLRP3
  gene_term:
    preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  association: Causative
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
  notes: >
    Muckle-Wells syndrome is caused by heterozygous gain-of-function missense
    mutations in NLRP3 (CIAS1, encoding cryopyrin). Inheritance is autosomal
    dominant; NLRP3 is the same gene underlying the milder FCAS and the severe
    CINCA/NOMID across the CAPS spectrum.
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS."
    explanation: Original identification of NLRP3/CIAS1 mutations segregating with disease in FCAS and MWS families, establishing NLRP3 as the causative gene.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Muckle-Wells syndrome follows autosomal dominant inheritance, caused by
    heterozygous gain-of-function NLRP3 variants.
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present."
    explanation: Original description establishing MWS as an autosomal-dominant periodic fever syndrome.
treatments:
- name: Anakinra
  description: >
    Recombinant IL-1 receptor antagonist (blocks IL-1alpha and IL-1beta), given
    daily; effective across the CAPS spectrum including MWS, rapidly controlling
    inflammation and normalizing acute-phase reactants.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: CHEBI:231683
        label: Anakinra
  target_mechanisms:
  - target: Caspase-1 activation and IL-1beta overproduction
    treatment_effect: INHIBITS
    description: >-
      Anakinra competitively blocks the IL-1 receptor, neutralizing the excess
      IL-1beta signaling produced by the constitutively active inflammasome.
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IL-1 blockade with anakinra, canakinumab, and rilonacept is standard of care in CAPS with a well-established safety profile."
    explanation: Establishes anakinra (IL-1 receptor antagonist) as a standard-of-care IL-1 blockade agent for CAPS, including MWS.
- name: Canakinumab
  description: >
    Anti-IL-1beta monoclonal antibody administered every 4-8 weeks; approved for
    CAPS. Reduces flares and normalizes CRP/SAA, and is the prototypical
    long-acting IL-1 blockade for MWS.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
  target_mechanisms:
  - target: Caspase-1 activation and IL-1beta overproduction
    treatment_effect: INHIBITS
    description: >-
      Canakinumab binds and neutralizes IL-1beta, the principal effector cytokine
      of the constitutively active NLRP3 inflammasome.
  evidence:
  - reference: PMID:39334417
    reference_title: "Effectiveness and safety of canakinumab in cryopyrin-associated periodic syndrome: a retrospective study in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After treatments, 60% (6/10) of CAPS patients achieved complete remission without relapse and the rest showed minimal disease activity."
    explanation: Real-world CAPS cohort showing canakinumab induces remission or minimal disease activity, supporting its efficacy for MWS.
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IL-1 blockade with anakinra, canakinumab, and rilonacept is standard of care in CAPS with a well-established safety profile."
    explanation: Establishes canakinumab (anti-IL-1beta monoclonal antibody) as a standard-of-care IL-1 blockade agent for CAPS, including MWS.
- name: Rilonacept
  description: >
    IL-1 trap (soluble decoy receptor capturing IL-1alpha and IL-1beta)
    administered weekly; reduces flares in the FCAS/MWS end of the CAPS spectrum.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Rilonacept
      term:
        id: NCIT:C84137
        label: Rilonacept
  target_mechanisms:
  - target: Caspase-1 activation and IL-1beta overproduction
    treatment_effect: INHIBITS
    description: >-
      Rilonacept acts as a soluble decoy receptor that sequesters IL-1beta (and
      IL-1alpha), blocking downstream IL-1 signaling from the inflammasome.
  evidence:
  - reference: PMID:32983099
    reference_title: "Human Autoinflammatory Diseases Mediated by NLRP3-, Pyrin-, NLRP1-, and NLRC4-Inflammasome Dysregulation Updates on Diagnosis, Treatment, and the Respective Roles of IL-1 and IL-18."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "IL-1 blockade with anakinra, canakinumab, and rilonacept is standard of care in CAPS with a well-established safety profile."
    explanation: Establishes rilonacept (IL-1 trap) as a standard-of-care IL-1 blockade agent for CAPS, including MWS.
- name: Genetic counseling
  description: >
    Autosomal dominant inheritance warrants genetic counseling for affected MWS
    families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS."
    explanation: Autosomal dominant segregation of NLRP3 mutations in MWS families supports genetic counseling.
differential_diagnoses:
- name: Familial cold autoinflammatory syndrome
  description: >
    The mildest CAPS phenotype, with cold-triggered urticarial episodes, fever,
    and arthralgia and, unlike MWS, generally without progressive hearing loss
    or amyloidosis.
  disease_term:
    preferred_term: familial cold autoinflammatory syndrome
    term:
      id: MONDO:0018768
      label: familial cold autoinflammatory syndrome
  evidence:
  - reference: PMID:11687797
    reference_title: "Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
    explanation: FCAS is the milder, cold-triggered CAPS phenotype distinguished from MWS, which is largely cold-independent and carries hearing loss and amyloidosis risk.
- name: CINCA syndrome
  description: >
    The most severe CAPS phenotype (NOMID), with neonatal-onset chronic aseptic
    meningitis, deforming arthropathy with epiphyseal overgrowth, and
    neurodevelopmental impairment absent in MWS.
  disease_term:
    preferred_term: CINCA syndrome
    term:
      id: MONDO:0011776
      label: CINCA syndrome
  evidence:
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "higher levels of acute phase reactants and severe articular and neurological involvement"
    explanation: CINCA/NOMID is distinguished from MWS by its severe articular and neurological (CNS) involvement and higher acute-phase reactants, features absent in the intermediate MWS phenotype.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008633
      label: Muckle-Wells syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO identifier for Muckle-Wells syndrome (matches disease_term).
  ncit_mappings:
  - term:
      id: NCIT:C84657
      label: Cryopyrin-Associated Periodic Syndrome
    mapping_predicate: skos:broadMatch
    mapping_source: NCIT
    mapping_justification: NCIT has no MWS-specific term; MWS is the intermediate phenotype of the CAPS spectrum captured by this parent concept.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.41
  rate_low: 0.27
  rate_high: 0.55
  notes: >-
    CAPS-spectrum estimate (2.7-5.5 per 1,000,000); MWS is the intermediate
    phenotype within CAPS and is not tabulated separately. The true prevalence
    is likely underestimated because CAPS is often misdiagnosed.
  evidence:
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ranging from 2.7 to 5.5 per 1 million and might be higher"
    explanation: Reports the CAPS-spectrum prevalence range (2.7-5.5 per million), placing MWS in the ultra-rare 1-9 per 1,000,000 band.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_nlrp3_il1_inflammasome_model
  hypothesis_label: Canonical NLRP3 Inflammasome / IL-1beta Model
  status: CANONICAL
  description: >-
    Gain-of-function NLRP3 mutations cause constitutive inflammasome assembly and
    caspase-1 activation, driving excessive IL-1beta production as the central
    effector of the systemic and organ-specific inflammation of MWS. The dominant
    pathogenic role of IL-1beta is established by the rapid clinical and
    biochemical response to IL-1 blockade.
review_notes: >-
  GeneReviews baseline check (re-verified 2026-08-29 against the NCBI GeneReviews
  A-to-Z / Bookshelf): GeneReviews has no dedicated chapter for Muckle-Wells
  syndrome, NLRP3-associated autoinflammatory disease, or the broader
  cryopyrin-associated periodic syndromes (CAPS). Related hereditary
  periodic-fever chapters (e.g. Familial Mediterranean Fever, TNF
  Receptor-Associated Periodic Fever Syndrome) exist, but none covers CAPS/NLRP3;
  the disorder is covered instead by primary reviews. No GeneReviews baseline is
  tagged. MWS is the intermediate phenotype of the CAPS spectrum; its sibling CAPS
  entries in this KB are Familial_Cold_Autoinflammatory_Syndrome (the mild end)
  and, for the severe end, the CINCA/NOMID differential (see
  differential_diagnoses). Created de novo (no deep-research provider used, per
  task constraints) from primary literature; snippets verified against cached
  references and ontology terms validated with OAK.
📚

References & Deep Research

References

3
PMID:11687797
Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome.
No top-level findings curated for this source.
PMID:33401496
Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?
No top-level findings curated for this source.
PMID:36275641
NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies.
No top-level findings curated for this source.