🏷

Classifications

Harrison's Chapter

◆

Subtypes

4

FCAS1 (NLRP3 / cryopyrin)

The classic and most common form of FCAS, caused by heterozygous gain-of-function mutations in NLRP3 (CIAS1, encoding cryopyrin). FCAS1 is the mildest phenotype on the cryopyrin-associated periodic syndrome (CAPS) spectrum. Inheritance is 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 CIAS1/NLRP3 mutations as the cause of FCAS, establishing the genetic basis of the classic FCAS1 subtype.

FCAS2 (NLRP12)

A cold-induced hereditary periodic fever syndrome caused by heterozygous NLRP12 (NALP12/Monarch-1) mutations, clinically resembling FCAS1 but genetically distinct. NLRP12 mutations impair NF-kappaB regulation.

Show evidence (1 reference)

PMID:18230725 SUPPORT Human Clinical

"we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes."

Original identification of NALP12 (NLRP12) mutations causing hereditary periodic fever syndromes (FCAS2).

FCAS3 (PLCG2)

A dominantly inherited syndrome caused by heterozygous PLCG2 deletions/mutations (PLCG2-associated antibody deficiency and immune dysregulation, PLAID), in which cold exposure triggers urticaria and leukocyte activation. PLCG2 deletions confer gain of phospholipase function at subphysiologic temperature.

Show evidence (1 reference)

PMID:22236196 SUPPORT Human Clinical

"Cold urticaria occurred in all affected subjects."

NEJM description of cold-induced urticaria in families with PLCG2 deletions, the basis of the FCAS3/PLAID subtype.

FCAS4 (NLRP1)

A rare autoinflammatory and autoimmune syndrome associated with NLRP1 mutations (NAIAD, NLRP1-associated autoinflammation with arthritis and dyskeratosis). NLRP1 mutations activate the NLRP1 inflammasome with elevated caspase-1 and IL-18.

Show evidence (1 reference)

PMID:27965258 SUPPORT Human Clinical

"We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis."

Original identification of NLRP1 mutations causing an autoinflammatory disorder, the basis of the FCAS4/NAIAD subtype.

⚙

Pathophysiology

7

NLRP3 gain-of-function mutation

Heterozygous gain-of-function 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. In FCAS1, generalized cold exposure triggers inappropriate inflammasome activation in myeloid cells.

Monocyte CL:0000576 Macrophage CL:0000235

NLRP3 hgnc:16400

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 NLRP3/CIAS1 domain architecture supporting its role as an inflammation regulator whose mutation causes FCAS.

PMID:36275641 SUPPORT Human Clinical

"Gain-of-function mutations in NLRP3 gene are causative of signs and inflammatory symptoms in CAPS patients"

Review confirming NLRP3 gain-of-function mutations as the cause of CAPS, including the FCAS phenotype.

Constitutive NLRP3 inflammasome activation

Mutant NLRP3 assembles the inflammasome complex with reduced/absent requirement for a second activating signal, especially following the environmental cold trigger characteristic of FCAS. Assembly recruits the adaptor ASC and pro-caspase-1.

Monocyte CL:0000576

NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED

Downstream

Caspase-1 activation and IL-1beta overproduction

Show evidence (1 reference)

PMID:38146057 SUPPORT Human Clinical

"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 inflammatory phenotype.

Interleukin-1 beta production GO:0032611 ↑ INCREASED Pyroptotic inflammatory response GO:0070269 ↑ INCREASED

Downstream

Systemic cold-triggered sterile inflammation

Show evidence (3 references)

PMID:36275641 SUPPORT In Vitro

"an abnormal activation of the NLRP3 inflammasome, resulting in an inappropriate release of IL-1β and gasdermin-D-dependent pyroptosis, has been demonstrated both in in vitro and in ex vivo studies."

In vitro/ex vivo evidence that mutant NLRP3 inflammasome activation drives inappropriate IL-1beta release and pyroptosis.

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.

PMID:32983099 SUPPORT In Vitro

"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.

Systemic cold-triggered sterile inflammation

The shared downstream phenotype on which all FCAS etiologies converge: episodic, cold-triggered systemic sterile inflammation. In NLRP3-driven FCAS1 this is principally IL-1-driven, whereas the NLRP12 (NF-kappaB dysregulation) and PLCG2 (cold-dependent leukocyte/mast-cell activation) etiologies act through parallel inflammatory pathways that are not strictly IL-1-dependent. Clinically it manifests as cold-triggered urticarial rash, low-grade fever, arthralgia/myalgia, and conjunctivitis; across the broader CAPS spectrum it can extend to sensorineural hearing loss, CNS inflammation, and AA amyloidosis.

Inflammatory response GO:0006954 ↑ INCREASED

Downstream

Urticarial rash Cold-triggered sterile inflammation produces intermittent urticarial rash.

Recurrent fever Cold-triggered systemic inflammation produces recurrent fever episodes.

Arthralgia Cold-triggered systemic inflammation produces episodic arthralgia.

Conjunctivitis Cold-triggered systemic inflammation produces conjunctivitis episodes.

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."

Defines the cold-triggered systemic inflammatory phenotype that results from dysregulated IL-1-driven inflammation in FCAS.

NLRP12-associated NF-kappaB dysregulation

In FCAS2, nonsense and splice-site mutations in NLRP12 (NALP12) have a deleterious effect on NF-kappaB signaling, producing a cold-associated hereditary periodic fever phenotype distinct from NLRP3-driven disease.

NLRP12 hgnc:22938

Downstream

Systemic cold-triggered sterile inflammation NLRP12-driven NF-kappaB dysregulation converges on the same cold-associated systemic autoinflammatory phenotype that characterizes the CAPS/FCAS spectrum, via NF-kappaB-regulated cytokines rather than strictly IL-1 alone.

Show evidence (1 reference)

PMID:18230725 SUPPORT In Vitro

"As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-kappaB signaling."

Functional evidence that FCAS2-causing NLRP12 mutations dysregulate NF-kappaB signaling.

PLCG2 cold-dependent gain of function

In FCAS3 (PLAID), in-frame genomic deletions in the PLCG2 autoinhibitory domain produce constitutively active phospholipase C-gamma-2. Affected cells show diminished signaling at 37C but enhanced signaling at subphysiologic temperatures, explaining cold-induced leukocyte activation and urticaria.

Mast cell CL:0000097

PLCG2 hgnc:9066

Downstream

Systemic cold-triggered sterile inflammation Cold-dependent PLCG2 gain of function drives mast-cell and leukocyte activation that feeds into the shared cold-triggered systemic inflammatory phenotype of the FCAS spectrum through a PLCgamma2-dependent pathway rather than IL-1beta overproduction.

Show evidence (2 references)

PMID:22236196 SUPPORT In Vitro

"PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures."

Demonstrates the temperature-dependent gain of PLCG2 function underlying cold-triggered inflammation in FCAS3.

PMID:22236196 SUPPORT In Vitro

"transfection with mutated PLCG2 into LAD2 mast cells, which endogenously express PLCγ2, led to spontaneous degranulation at 20°C"

Mutant PLCG2 drives spontaneous mast-cell degranulation at subphysiologic temperature, the cellular basis of cold-triggered urticaria in FCAS3/PLAID.

NLRP1 inflammasome activation

In FCAS4 (NAIAD), NLRP1 mutations activate the NLRP1 inflammasome, with elevated systemic caspase-1 and IL-18, producing autoinflammation with arthritis and skin dyskeratosis.

NLRP1 hgnc:14374

Interleukin-18 production GO:0032621 ↑ INCREASED

Downstream

Caspase-1 activation and IL-1beta overproduction Activation of the NLRP1 inflammasome raises systemic caspase-1 and IL-18, converging on the caspase-1/IL-1 axis that drives FCAS-spectrum autoinflammation.

Show evidence (1 reference)

PMID:27965258 SUPPORT Human Clinical

"The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome."

Evidence that NLRP1 mutations in FCAS4/NAIAD drive caspase-1 and IL-18 elevation via the NLRP1 inflammasome.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

8

Cardiovascular 2

Urticarial rash Urticaria HP:0001025

Temporal: RECURRENT

Show evidence (2 references)

PMID:11687797 SUPPORT Human Clinical

"intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."

FCAS is defined by intermittent cold-triggered rash among its core features.

PMID:36275641 SUPPORT Human Clinical

"urticaria-like skin biopsies showed a predominance of neutrophils in early-stage lesions while lymphocytes in long-standing ones"

Skin histopathology confirms the FCAS rash is a neutrophil-predominant (pseudo-urticarial) infiltrate rather than a classic mast-cell-driven wheal.

Conjunctivitis Conjunctivitis HP:0000509

Show evidence (2 references)

PMID:11687797 SUPPORT Human Clinical

"intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."

Conjunctivitis is a defining core feature of FCAS attacks.

PMID:32983099 SUPPORT Human Clinical

"neutrophilic urticaria, fever, conjunctivitis, and arthralgia"

Inflammasome review confirming conjunctivitis as part of the CAPS clinical presentation alongside neutrophilic urticaria, fever, and arthralgia.

Ear 1

Sensorineural hearing loss Sensorineural hearing impairment HP:0000407

Course: PROGRESSIVE

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."

Establishes sensorineural hearing loss as a feature of the more severe CAPS phenotypes contiguous with FCAS.

Metabolism 1

Recurrent fever Recurrent fever HP:0001954

Show evidence (1 reference)

PMID:11687797 SUPPORT Human Clinical

"intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."

Fever is a defining intermittent feature of FCAS attacks.

Constitutional 2

Arthralgia Arthralgia HP:0002829

Show evidence (1 reference)

PMID:11687797 SUPPORT Human Clinical

"intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."

Arthralgia is a defining core feature of FCAS attacks.

Myalgia Myalgia HP:0003326

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 in a clinical CAPS cohort.

Other 2

Elevated C-reactive protein Elevated circulating C-reactive protein concentration HP:0011227

Show evidence (1 reference)

PMID:39334417 SUPPORT Human Clinical

"Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels."

CRP and SAA are the acute-phase reactants used to assess CAPS inflammatory activity and treatment response.

Renal amyloidosis Renal amyloidosis HP:0001917

Show evidence (1 reference)

PMID:36275641 SUPPORT Human Clinical

"progressive sensorineural hearing loss and the tendency to develop renal amyloidosis, with the increase of serum levels of amyloid A protein (SAA)"

Renal amyloidosis driven by sustained serum amyloid A elevation is the most serious long-term CAPS complication (classically Muckle-Wells syndrome); it is rare in mild FCAS but defines the disease spectrum.

🧬

Genetic Associations

4

NLRP3 (Causative)

Gene: NLRP3 hgnc:16400

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 as the causative gene for FCAS.

NLRP12 (Causative)

Gene: NLRP12 hgnc:22938

Autosomal dominant

Show evidence (1 reference)

PMID:18230725 SUPPORT Human Clinical

"Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders."

Identification of NLRP12 as the gene defining the FCAS2 periodic fever group.

PLCG2 (Causative)

Gene: PLCG2 hgnc:9066

Autosomal dominant

Show evidence (1 reference)

PMID:22236196 SUPPORT Human Clinical

"Genomic deletions in PLCG2 cause gain of PLCγ(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function."

Establishes PLCG2 gain-of-function deletions as the cause of the FCAS3/PLAID cold urticaria phenotype.

NLRP1 (Causative)

Gene: NLRP1 hgnc:14374

Autosomal dominant Autosomal recessive

Show evidence (1 reference)

PMID:27965258 SUPPORT Human Clinical

"Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin."

Identification of causative NLRP1 mutations in FCAS4/NAIAD.

💊

Medical Actions

5

Anakinra

Action: Pharmacotherapy NCIT:C15986

Agent: anakinra CHEBI:231683

Recombinant IL-1 receptor antagonist (blocks IL-1alpha and IL-1beta), given daily; effective across the CAPS spectrum including FCAS.

Show evidence (2 references)

PMID:38146057 SUPPORT Human Clinical

"The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein."

Confirms IL-1-targeted therapies (including anakinra) are successfully used to treat CAPS.

PMID:32983099 SUPPORT Human Clinical

"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.

Canakinumab

Action: Pharmacotherapy NCIT:C15986

Agent: canakinumab NCIT:C80971

Anti-IL-1beta monoclonal antibody administered every 4-8 weeks; FDA/EMA approved for CAPS phenotypes. Reduces flares and normalizes CRP/SAA.

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 cohort (including an FCAS patient) showing canakinumab induces remission in CAPS.

PMID:32983099 SUPPORT Human Clinical

"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.

Rilonacept

Action: Pharmacotherapy NCIT:C15986

Agent: rilonacept NCIT:C84137

IL-1 trap (soluble decoy receptor) administered weekly; reduces flares in FCAS/MWS with sustained response.

Show evidence (2 references)

PMID:38146057 SUPPORT Human Clinical

"The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein."

Confirms targeted IL-1 therapies (including the IL-1 trap rilonacept) are established CAPS treatments.

PMID:32983099 SUPPORT Human Clinical

"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.

Genetic counseling

Action: Genetic Counseling NCIT:C15240

Autosomal dominant inheritance warrants genetic counseling for affected families across all FCAS subtypes.

Show evidence (1 reference)

PMID:38343435 SUPPORT Human Clinical

"Cryopyrin-associated periodic syndrome or NLRP3-associated autoinflammatory disease (NLRP3-AID) and NLRP12-AID are both Mendelian disorders with autosomal dominant inheritance."

Autosomal dominant Mendelian inheritance of FCAS subtypes supports genetic counseling for families.

Cold avoidance

Action: supportive care MAXO:0000950

Avoidance of generalized cold exposure reduces the frequency of cold-triggered FCAS attacks as a non-pharmacological supportive measure.

Show evidence (1 reference)

PMID:11687797 SUPPORT Human Clinical

"intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."

Because attacks follow generalized cold exposure, avoiding cold is a logical supportive intervention.

🌍

Environmental Factors

1

Generalized cold exposure

Generalized cold exposure is the characteristic (near-pathognomonic) trigger of FCAS inflammatory attacks; in FCAS3, cold drives temperature-dependent PLCG2 activation.

Show evidence (1 reference)

PMID:22236196 SUPPORT Human Clinical

"Cold urticaria occurred in all affected subjects."

Cold exposure is the defining environmental trigger of urticaria in the cold autoinflammatory spectrum (PLCG2/FCAS3 cohort).

🔬

Biochemical Markers

2

C-reactive protein (PRESENT)

Show evidence (1 reference)

PMID:39334417 SUPPORT Human Clinical

"Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels."

CRP is a core biochemical marker of disease activity in CAPS.

Serum amyloid A (PRESENT)

Show evidence (1 reference)

PMID:39334417 SUPPORT Human Clinical

"Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels."

SAA is a core biochemical marker of disease activity used to guide CAPS therapy.

{ }

Source YAML

click to show

name: Familial Cold Autoinflammatory Syndrome
creation_date: '2026-06-16T00:00:00Z'
category: Mendelian
synonyms:
- FCAS
- Familial cold urticaria
- FCU
- Familial cold-induced autoinflammatory syndrome
- Familial polymorphous cold eruption
disease_term:
  preferred_term: familial cold autoinflammatory syndrome
  term:
    id: MONDO:0018768
    label: familial cold autoinflammatory syndrome
parents:
- Autoinflammatory diseases
- Cryopyrin-associated periodic syndromes
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:34198614
      reference_title: "Monogenic Autoinflammatory Diseases: State of the Art and Future Perspectives."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways."
      explanation: FCAS is a monogenic systemic autoinflammatory disease driven by innate immune dysregulation, placing it in Harrison's immune-mediated and inflammatory disorders chapter.
description: >
  Familial cold autoinflammatory syndrome (FCAS) is a dominantly inherited
  autoinflammatory disorder characterized by recurrent, cold-triggered episodes
  of urticaria-like skin rash, low-grade fever, arthralgia/myalgia, and
  conjunctivitis. FCAS1 (NLRP3/cryopyrin) is the mildest disorder on the
  cryopyrin-associated periodic syndrome (CAPS) spectrum, which also includes
  Muckle-Wells syndrome and CINCA/NOMID. The shared mechanism is inappropriate
  activation of the NLRP3 inflammasome with caspase-1-dependent overproduction of
  IL-1beta. Genetically distinct FCAS-like cold-triggered syndromes are caused by
  mutations in NLRP12 (FCAS2), PLCG2 (FCAS3), and NLRP1 (FCAS4).
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:38146057
  title: "The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity."
- reference: PMID:36275641
  title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
  findings:
  - statement: In North America up to 75% of CAPS patients have the mild FCAS phenotype, largely attributable to a recurrent NLRP3 founder mutation.
    supporting_text: "up to 75% of CAPS patients in North America are diagnosed as FCAS, due to a founder mutation (p.Leu353Pro) in NLRP3 gene"
    evidence:
    - reference: PMID:36275641
      reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "up to 75% of CAPS patients in North America are diagnosed as FCAS, due to a founder mutation (p.Leu353Pro) in NLRP3 gene"
      explanation: Documents FCAS epidemiology and the p.Leu353Pro NLRP3 founder mutation underlying the high North American FCAS frequency.
  - statement: FCAS attacks begin within about two hours of generalized cold exposure.
    supporting_text: "The symptoms usually start 2 hours after cold exposure"
    evidence:
    - reference: PMID:36275641
      reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The symptoms usually start 2 hours after cold exposure"
      explanation: Characterizes the short latency between generalized cold exposure and FCAS attack onset.
has_subtypes:
- name: FCAS1
  display_name: FCAS1 (NLRP3 / cryopyrin)
  description: >
    The classic and most common form of FCAS, caused by heterozygous
    gain-of-function mutations in NLRP3 (CIAS1, encoding cryopyrin). FCAS1 is the
    mildest phenotype on the cryopyrin-associated periodic syndrome (CAPS)
    spectrum. Inheritance is autosomal dominant.
  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 CIAS1/NLRP3 mutations as the cause of FCAS, establishing the genetic basis of the classic FCAS1 subtype.
- name: FCAS2
  display_name: FCAS2 (NLRP12)
  description: >
    A cold-induced hereditary periodic fever syndrome caused by heterozygous
    NLRP12 (NALP12/Monarch-1) mutations, clinically resembling FCAS1 but
    genetically distinct. NLRP12 mutations impair NF-kappaB regulation.
  evidence:
  - reference: PMID:18230725
    reference_title: "Mutations in NALP12 cause hereditary periodic fever syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes."
    explanation: Original identification of NALP12 (NLRP12) mutations causing hereditary periodic fever syndromes (FCAS2).
- name: FCAS3
  display_name: FCAS3 (PLCG2)
  description: >
    A dominantly inherited syndrome caused by heterozygous PLCG2 deletions/mutations
    (PLCG2-associated antibody deficiency and immune dysregulation, PLAID), in
    which cold exposure triggers urticaria and leukocyte activation. PLCG2
    deletions confer gain of phospholipase function at subphysiologic temperature.
  evidence:
  - reference: PMID:22236196
    reference_title: "Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cold urticaria occurred in all affected subjects."
    explanation: NEJM description of cold-induced urticaria in families with PLCG2 deletions, the basis of the FCAS3/PLAID subtype.
- name: FCAS4
  display_name: FCAS4 (NLRP1)
  description: >
    A rare autoinflammatory and autoimmune syndrome associated with NLRP1
    mutations (NAIAD, NLRP1-associated autoinflammation with arthritis and
    dyskeratosis). NLRP1 mutations activate the NLRP1 inflammasome with elevated
    caspase-1 and IL-18.
  evidence:
  - reference: PMID:27965258
    reference_title: "A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis."
    explanation: Original identification of NLRP1 mutations causing an autoinflammatory disorder, the basis of the FCAS4/NAIAD subtype.
pathophysiology:
- name: NLRP3 gain-of-function mutation
  description: >
    Heterozygous gain-of-function 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. In FCAS1,
    generalized cold exposure triggers inappropriate inflammasome activation in
    myeloid cells.
  subtypes:
  - FCAS1
  gene:
    preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  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 NLRP3/CIAS1 domain architecture supporting its role as an inflammation regulator whose mutation causes FCAS.
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gain-of-function mutations in NLRP3 gene are causative of signs and inflammatory symptoms in CAPS patients"
    explanation: Review confirming NLRP3 gain-of-function mutations as the cause of CAPS, including the FCAS phenotype.
- name: Constitutive NLRP3 inflammasome activation
  description: >
    Mutant NLRP3 assembles the inflammasome complex with reduced/absent
    requirement for a second activating signal, especially following the
    environmental cold trigger characteristic of FCAS. Assembly recruits the
    adaptor ASC and pro-caspase-1.
  subtypes:
  - FCAS1
  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: HUMAN_CLINICAL
    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
  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 inflammatory phenotype.
  subtypes:
  - FCAS1
  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 cold-triggered sterile inflammation
  evidence:
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "an abnormal activation of the NLRP3 inflammasome, resulting in an inappropriate release of IL-1β and gasdermin-D-dependent pyroptosis, has been demonstrated both in in vitro and in ex vivo studies."
    explanation: In vitro/ex vivo evidence that mutant NLRP3 inflammasome activation drives inappropriate IL-1beta release and pyroptosis.
  - 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.
  - 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: IN_VITRO
    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.
- name: Systemic cold-triggered sterile inflammation
  description: >
    The shared downstream phenotype on which all FCAS etiologies converge:
    episodic, cold-triggered systemic sterile inflammation. In NLRP3-driven
    FCAS1 this is principally IL-1-driven, whereas the NLRP12 (NF-kappaB
    dysregulation) and PLCG2 (cold-dependent leukocyte/mast-cell activation)
    etiologies act through parallel inflammatory pathways that are not strictly
    IL-1-dependent. Clinically it manifests as cold-triggered urticarial rash,
    low-grade fever, arthralgia/myalgia, and conjunctivitis; across the broader
    CAPS spectrum it can extend to sensorineural hearing loss, CNS inflammation,
    and AA amyloidosis.
  subtypes:
  - FCAS1
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  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: Defines the cold-triggered systemic inflammatory phenotype that results from dysregulated IL-1-driven inflammation in FCAS.
  downstream:
  - target: Urticarial rash
    causal_link_type: DIRECT
    description: Cold-triggered sterile inflammation produces intermittent urticarial rash.
    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: Supports rash after cold exposure as a cardinal FCAS manifestation.
  - target: Recurrent fever
    causal_link_type: DIRECT
    description: Cold-triggered systemic inflammation produces recurrent fever episodes.
    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: Supports fever after cold exposure as a cardinal FCAS manifestation.
  - target: Arthralgia
    causal_link_type: DIRECT
    description: Cold-triggered systemic inflammation produces episodic arthralgia.
    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: Supports arthralgia after cold exposure as a cardinal FCAS manifestation.
  - target: Conjunctivitis
    causal_link_type: DIRECT
    description: Cold-triggered systemic inflammation produces conjunctivitis episodes.
    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: Supports conjunctivitis after cold exposure as a cardinal FCAS manifestation.
- name: NLRP12-associated NF-kappaB dysregulation
  description: >
    In FCAS2, nonsense and splice-site mutations in NLRP12 (NALP12) have a
    deleterious effect on NF-kappaB signaling, producing a cold-associated
    hereditary periodic fever phenotype distinct from NLRP3-driven disease.
  subtypes:
  - FCAS2
  gene:
    preferred_term: NLRP12
    term:
      id: hgnc:22938
      label: NLRP12
  evidence:
  - reference: PMID:18230725
    reference_title: "Mutations in NALP12 cause hereditary periodic fever syndromes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-kappaB signaling."
    explanation: Functional evidence that FCAS2-causing NLRP12 mutations dysregulate NF-kappaB signaling.
  downstream:
  - target: Systemic cold-triggered sterile inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: NLRP12-driven NF-kappaB dysregulation converges on the same cold-associated systemic autoinflammatory phenotype that characterizes the CAPS/FCAS spectrum, via NF-kappaB-regulated cytokines rather than strictly IL-1 alone.
- name: PLCG2 cold-dependent gain of function
  description: >
    In FCAS3 (PLAID), in-frame genomic deletions in the PLCG2 autoinhibitory
    domain produce constitutively active phospholipase C-gamma-2. Affected cells
    show diminished signaling at 37C but enhanced signaling at subphysiologic
    temperatures, explaining cold-induced leukocyte activation and urticaria.
  subtypes:
  - FCAS3
  gene:
    preferred_term: PLCG2
    term:
      id: hgnc:9066
      label: PLCG2
  cell_types:
  - preferred_term: Mast cell
    term:
      id: CL:0000097
      label: mast cell
  evidence:
  - reference: PMID:22236196
    reference_title: "Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures."
    explanation: Demonstrates the temperature-dependent gain of PLCG2 function underlying cold-triggered inflammation in FCAS3.
  - reference: PMID:22236196
    reference_title: "Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "transfection with mutated PLCG2 into LAD2 mast cells, which endogenously express PLCγ2, led to spontaneous degranulation at 20°C"
    explanation: Mutant PLCG2 drives spontaneous mast-cell degranulation at subphysiologic temperature, the cellular basis of cold-triggered urticaria in FCAS3/PLAID.
  downstream:
  - target: Systemic cold-triggered sterile inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Cold-dependent PLCG2 gain of function drives mast-cell and leukocyte activation that feeds into the shared cold-triggered systemic inflammatory phenotype of the FCAS spectrum through a PLCgamma2-dependent pathway rather than IL-1beta overproduction.
- name: NLRP1 inflammasome activation
  description: >
    In FCAS4 (NAIAD), NLRP1 mutations activate the NLRP1 inflammasome, with
    elevated systemic caspase-1 and IL-18, producing autoinflammation with
    arthritis and skin dyskeratosis.
  subtypes:
  - FCAS4
  gene:
    preferred_term: NLRP1
    term:
      id: hgnc:14374
      label: NLRP1
  biological_processes:
  - preferred_term: Interleukin-18 production
    term:
      id: GO:0032621
      label: interleukin-18 production
    modifier: INCREASED
  evidence:
  - reference: PMID:27965258
    reference_title: "A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome."
    explanation: Evidence that NLRP1 mutations in FCAS4/NAIAD drive caspase-1 and IL-18 elevation via the NLRP1 inflammasome.
  downstream:
  - target: Caspase-1 activation and IL-1beta overproduction
    causal_link_type: DIRECT
    description: Activation of the NLRP1 inflammasome raises systemic caspase-1 and IL-18, converging on the caspase-1/IL-1 axis that drives FCAS-spectrum autoinflammation.
phenotypes:
- name: Urticarial rash
  description: >
    Cold-triggered urticaria-like (often neutrophilic) skin rash is the
    cardinal cutaneous manifestation of FCAS.
  phenotype_term:
    preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
    temporality: RECURRENT
  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: "intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
    explanation: FCAS is defined by intermittent cold-triggered rash among its core features.
  - reference: PMID:36275641
    reference_title: "NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "urticaria-like skin biopsies showed a predominance of neutrophils in early-stage lesions while lymphocytes in long-standing ones"
    explanation: Skin histopathology confirms the FCAS rash is a neutrophil-predominant (pseudo-urticarial) infiltrate rather than a classic mast-cell-driven wheal.
- name: Recurrent fever
  description: Low-grade fever during cold-triggered inflammatory attacks.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  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: "intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
    explanation: Fever is a defining intermittent feature of FCAS attacks.
- name: Arthralgia
  description: Joint pain and transient joint stiffness during attacks.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  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: "intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
    explanation: Arthralgia is a defining core feature of FCAS attacks.
- name: Conjunctivitis
  description: >
    Ocular inflammation (conjunctivitis / red eye) is a common feature of FCAS
    and the broader CAPS spectrum.
  phenotype_term:
    preferred_term: Conjunctivitis
    term:
      id: HP:0000509
      label: Conjunctivitis
  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: "intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
    explanation: Conjunctivitis is a defining core feature of FCAS attacks.
  - 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: HUMAN_CLINICAL
    snippet: "neutrophilic urticaria, fever, conjunctivitis, and arthralgia"
    explanation: Inflammasome review confirming conjunctivitis as part of the CAPS clinical presentation alongside neutrophilic urticaria, fever, and arthralgia.
- name: Myalgia
  description: Muscle pain during cold-triggered 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 in a clinical CAPS cohort.
- name: Elevated C-reactive protein
  category: Laboratory
  description: >
    Elevated acute-phase reactants (CRP and serum amyloid A) accompany 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: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: "Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels."
    explanation: CRP and SAA are the acute-phase reactants used to assess CAPS inflammatory activity and treatment response.
- name: Sensorineural hearing loss
  description: >
    Progressive sensorineural hearing loss is a complication of more severe CAPS
    phenotypes (Muckle-Wells syndrome and NOMID/CINCA); it is uncommon in mild
    FCAS but defines the disease spectrum.
  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: Establishes sensorineural hearing loss as a feature of the more severe CAPS phenotypes contiguous with FCAS.
- name: Renal amyloidosis
  description: >
    Long-standing uncontrolled inflammation can lead to AA (secondary)
    amyloidosis with renal involvement, the most serious long-term complication
    across the CAPS spectrum.
  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: HUMAN_CLINICAL
    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 amyloidosis driven by sustained serum amyloid A elevation is the most serious long-term CAPS complication (classically Muckle-Wells syndrome); it is rare in mild FCAS but defines the disease spectrum.
genetic:
- name: NLRP3
  gene_term:
    preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  association: Causative
  presence: PRESENT
  subtype: FCAS1
  inheritance:
  - name: Autosomal dominant
  notes: >
    Heterozygous gain-of-function missense mutations in NLRP3 (CIAS1) cause
    FCAS1, the classic and most common form. NLRP3 encodes cryopyrin.
  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 as the causative gene for FCAS.
- name: NLRP12
  gene_term:
    preferred_term: NLRP12
    term:
      id: hgnc:22938
      label: NLRP12
  association: Causative
  presence: PRESENT
  subtype: FCAS2
  inheritance:
  - name: Autosomal dominant
  notes: >
    Heterozygous NLRP12 (NALP12) nonsense and splice-site mutations cause FCAS2,
    impairing NF-kappaB regulation.
  evidence:
  - reference: PMID:18230725
    reference_title: "Mutations in NALP12 cause hereditary periodic fever syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders."
    explanation: Identification of NLRP12 as the gene defining the FCAS2 periodic fever group.
- name: PLCG2
  gene_term:
    preferred_term: PLCG2
    term:
      id: hgnc:9066
      label: PLCG2
  association: Causative
  presence: PRESENT
  subtype: FCAS3
  inheritance:
  - name: Autosomal dominant
  notes: >
    Heterozygous in-frame genomic deletions in PLCG2 cause FCAS3 (PLAID), with
    gain of phospholipase C-gamma-2 function at subphysiologic temperature.
  evidence:
  - reference: PMID:22236196
    reference_title: "Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genomic deletions in PLCG2 cause gain of PLCγ(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function."
    explanation: Establishes PLCG2 gain-of-function deletions as the cause of the FCAS3/PLAID cold urticaria phenotype.
- name: NLRP1
  gene_term:
    preferred_term: NLRP1
    term:
      id: hgnc:14374
      label: NLRP1
  association: Causative
  presence: PRESENT
  subtype: FCAS4
  inheritance:
  - name: Autosomal dominant
  - name: Autosomal recessive
  notes: >
    NLRP1 mutations cause FCAS4 (NAIAD), activating the NLRP1 inflammasome.
    Reported families include both homozygous (recessive, consanguineous) and de
    novo heterozygous mutations.
  evidence:
  - reference: PMID:27965258
    reference_title: "A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin."
    explanation: Identification of causative NLRP1 mutations in FCAS4/NAIAD.
environmental:
- name: Generalized cold exposure
  description: >
    Generalized cold exposure is the characteristic (near-pathognomonic) trigger
    of FCAS inflammatory attacks; in FCAS3, cold drives temperature-dependent
    PLCG2 activation.
  presence: PRESENT
  effect: HARMFUL
  evidence:
  - reference: PMID:22236196
    reference_title: "Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cold urticaria occurred in all affected subjects."
    explanation: Cold exposure is the defining environmental trigger of urticaria in the cold autoinflammatory spectrum (PLCG2/FCAS3 cohort).
biochemical:
- name: C-reactive protein
  notes: >
    Acute-phase reactant elevated during inflammatory attacks; used with serum
    amyloid A to assess CAPS disease activity and treatment response.
  presence: PRESENT
  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: "Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels."
    explanation: CRP is a core biochemical marker of disease activity in CAPS.
- name: Serum amyloid A
  notes: >
    Acute-phase reactant; sustained elevation drives AA amyloidosis risk, making
    SAA normalization a treat-to-target goal.
  presence: PRESENT
  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: "Treatment response was evaluated by CAPS disease activity score, C-reactive protein (CRP), and/or serum amyloid A (SAA) levels."
    explanation: SAA is a core biochemical marker of disease activity used to guide CAPS therapy.
treatments:
- name: Anakinra
  description: >
    Recombinant IL-1 receptor antagonist (blocks IL-1alpha and IL-1beta), given
    daily; effective across the CAPS spectrum including FCAS.
  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
  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: HUMAN_CLINICAL
    snippet: "The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein."
    explanation: Confirms IL-1-targeted therapies (including anakinra) are successfully used to treat CAPS.
  - 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: HUMAN_CLINICAL
    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.
- name: Canakinumab
  description: >
    Anti-IL-1beta monoclonal antibody administered every 4-8 weeks; FDA/EMA
    approved for CAPS phenotypes. Reduces flares and normalizes CRP/SAA.
  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
  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 cohort (including an FCAS patient) showing canakinumab induces remission in CAPS.
  - 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: HUMAN_CLINICAL
    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.
- name: Rilonacept
  description: >
    IL-1 trap (soluble decoy receptor) administered weekly; reduces flares in
    FCAS/MWS with sustained response.
  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
  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: HUMAN_CLINICAL
    snippet: "The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein."
    explanation: Confirms targeted IL-1 therapies (including the IL-1 trap rilonacept) are established CAPS treatments.
  - 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: HUMAN_CLINICAL
    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.
- name: Genetic counseling
  description: >
    Autosomal dominant inheritance warrants genetic counseling for affected
    families across all FCAS subtypes.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38343435
    reference_title: "Genetic variations in NLRP3 and NLRP12 genes in adult-onset patients with autoinflammatory diseases: a comparative study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cryopyrin-associated periodic syndrome or NLRP3-associated autoinflammatory disease (NLRP3-AID) and NLRP12-AID are both Mendelian disorders with autosomal dominant inheritance."
    explanation: Autosomal dominant Mendelian inheritance of FCAS subtypes supports genetic counseling for families.
- name: Cold avoidance
  description: >
    Avoidance of generalized cold exposure reduces the frequency of
    cold-triggered FCAS attacks as a non-pharmacological supportive measure.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  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: "intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold."
    explanation: Because attacks follow generalized cold exposure, avoiding cold is a logical supportive intervention.

📚

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:38146057

The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity.

No top-level findings curated for this source.

PMID:36275641

NLRP3 inflammasome and NLRP3-related autoinflammatory diseases: From cryopyrin function to targeted therapies.

2 findings

In North America up to 75% of CAPS patients have the mild FCAS phenotype, largely attributable to a recurrent NLRP3 founder mutation.

"up to 75% of CAPS patients in North America are diagnosed as FCAS, due to a founder mutation (p.Leu353Pro) in NLRP3 gene"

Show evidence (1 reference)

PMID:36275641 SUPPORT Human Clinical

"up to 75% of CAPS patients in North America are diagnosed as FCAS, due to a founder mutation (p.Leu353Pro) in NLRP3 gene"

Documents FCAS epidemiology and the p.Leu353Pro NLRP3 founder mutation underlying the high North American FCAS frequency.

FCAS attacks begin within about two hours of generalized cold exposure.

"The symptoms usually start 2 hours after cold exposure"

Show evidence (1 reference)

PMID:36275641 SUPPORT Human Clinical

"The symptoms usually start 2 hours after cold exposure"

Characterizes the short latency between generalized cold exposure and FCAS attack onset.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 33 citations 2026-06-16T10:10:02.419550

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Familial Cold Autoinflammatory Syndrome
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Familial Cold Autoinflammatory Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: Familial Cold Autoinflammatory Syndrome (FCAS)

Executive summary

Familial Cold Autoinflammatory Syndrome (FCAS) is the mildest phenotype in the cryopyrin-associated periodic syndromes (CAPS) spectrum (also termed NLRP3-associated autoinflammatory disease, NLRP3-AID) caused most commonly by heterozygous gain-of-function variants in NLRP3 that drive inappropriate inflammasome activation and excess IL-1β/IL-18 signaling, leading to cold-triggered episodic systemic inflammation characterized by urticarial-like rash, fever, arthralgia/myalgia, and ocular inflammation (e.g., conjunctivitis). (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 1-3, moltrasio2022nlrp3inflammasomeand pages 1-2)

A compact knowledge-base–oriented facts table is provided below.

Domain	Key facts
Disease / classification	Familial Cold Autoinflammatory Syndrome (FCAS) is the mildest phenotype within cryopyrin-associated periodic syndromes (CAPS), now often grouped under NLRP3-associated autoinflammatory disease (NLRP3-AID); spectrum also includes Muckle-Wells syndrome (MWS) and CINCA/NOMID (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 1-3, moltrasio2022nlrp3inflammasomeand pages 1-2)
Identifiers	MONDO: familial cold autoinflammatory syndrome = MONDO:0018768; subtype concept familial cold autoinflammatory syndrome 1 = MONDO:0007349; core disease gene: NLRP3; additional FCAS-like subtype associations reported for PLCG2 and NLRC4 in MONDO/Open Targets disease mapping (OpenTargets Search: Familial cold autoinflammatory syndrome,Cryopyrin-associated periodic syndrome)
Common synonyms	FCAS; familial cold urticaria; familial cold-induced autoinflammatory syndrome; CAPS; cryopyrinopathy; NLRP3-associated autoinflammatory disease / NLRP3-AID (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 1-3, putnam2024thediscoveryof pages 3-4)
Inheritance / etiology	Usually autosomal dominant; typically caused by heterozygous gain-of-function NLRP3 variants causing constitutive inflammasome activation. Somatic mosaicism can occur and may explain mutation-negative or atypical cases (donato2021monogenicautoinflammatorydiseases pages 13-14, alehashemi2020humanautoinflammatorydiseases pages 3-5, delplanque2023diagnosticandtherapeutic pages 5-9)
Core clinical features	Recurrent cold-triggered inflammatory episodes with urticarial-like rash, low-grade fever, limb pain, transient joint stiffness, arthralgia/myalgia, and conjunctivitis/red eye; symptoms often worsen later in the day after generalized cold exposure (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 1-3, donato2021monogenicautoinflammatorydiseases pages 13-14)
Trigger pattern	Generalized cold exposure is the classic pathognomonic trigger for FCAS; attacks are typically brief and self-limited compared with more severe CAPS phenotypes (meertens2024theriddleof pages 7-8, ontario2022…ofthe pages 15-18, fonollosa2024updateonocular pages 4-6)
Key complications / organ involvement	Across CAPS spectrum: sensorineural hearing loss, ocular inflammation, chronic aseptic meningitis/CNS inflammation, skeletal abnormalities in severe disease, and AA amyloidosis; MWS has reported amyloidosis risk of ~25% if untreated (donato2021monogenicautoinflammatorydiseases pages 13-14, meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 3-4)
Ocular involvement	Eye involvement reported in 71% of CAPS cases in Eurofever registry; conjunctivitis most common (~62%), uveitis ~28%, papilledema/papillitis ~27%, keratitis ~10.6% (fonollosa2024updateonocular pages 4-6, fonollosa2024updateonocular pages 6-7)
Diagnostic markers / workup	Diagnosis relies on compatible phenotype plus elevated CRP and serum amyloid A (SAA) / other acute-phase reactants; classification can be made with raised CRP/SAA plus key signs even without molecular confirmation, while a pathogenic NLRP3 variant lowers the clinical threshold required. Deep/NGS testing is preferred because Sanger may miss mosaicism (meertens2024theriddleof pages 7-8, ontario2022…ofthe pages 18-20, delplanque2023diagnosticandtherapeutic pages 5-9)
Differential diagnosis clues	Distinguish from acquired cold urticaria (FCAS often has negative ice-cube test), and consider other monogenic AIDs such as NLRP12-AID, TRAPS, MKD, DIRA, plus autoimmune, infectious, and neoplastic mimics (ontario2022…ofthe pages 15-18, ontario2022…ofthe pages 13-15, delplanque2023diagnosticandtherapeutic pages 1-5)
Pathophysiology	NLRP3 gain-of-function drives spontaneous inflammasome assembly with increased caspase-1, excess IL-1β and IL-18, and gasdermin-D-dependent pyroptosis, producing systemic sterile inflammation (putnam2024thediscoveryof pages 1-3, moltrasio2022nlrp3inflammasomeand pages 1-2)
Epidemiology	Combined CAPS prevalence is reported as approximately 1/360,000; FCAS is rare and usually begins in infancy/childhood (meertens2024theriddleof pages 7-8)
Targeted treatment classes	Standard targeted therapy is IL-1 blockade: anakinra (IL-1 receptor antagonist, daily), rilonacept (IL-1 trap, weekly), canakinumab (anti-IL-1β monoclonal antibody, every 4–8 weeks). Early long-term IL-1 inhibition is recommended across CAPS spectrum (alehashemi2020humanautoinflammatorydiseases pages 3-5, moltrasio2022nlrp3inflammasomeand pages 11-13, cinar2022hereditarysystemicautoinflammatory pages 5-7)
Canakinumab key trial / cohort outcomes	Placebo-controlled trial: at week 24, all canakinumab-treated patients remained in remission vs 25% on placebo; large 166-patient cohort: 78% persistent clinical remission with no organ-damage progression; early RCT: 34/35 CAPS patients achieved remission (moltrasio2022nlrp3inflammasomeand pages 11-13, cinar2022hereditarysystemicautoinflammatory pages 5-7)
Rilonacept key outcomes	In FCAS/MWS studies, rilonacept reduced flares/symptoms in 84% of treated patients vs placebo and responses were sustained up to 2 years (moltrasio2022nlrp3inflammasomeand pages 11-13)
Anakinra key outcomes	Observational CAPS cohorts report complete/partial remission 40–100%; sustained remission over 3–5 years reported in NOMID/CINCA cohorts; useful when broader IL-1α/IL-1β blockade is desired (moltrasio2022nlrp3inflammasomeand pages 11-13, ontario2022…ofthe pages 23-26)
2024 real-world canakinumab data (China)	Single-center retrospective cohort, 10 CAPS patients (including 1 FCAS): median follow-up 22.5 months; 60% (6/10) complete remission without relapse; remainder minimal disease activity; fever/rash improved in ~80%; 30% (3/10) required dose escalation; prednisone use fell from 60% to 10%; infections in 40%; no serious adverse events (zhu2024effectivenessandsafety pages 2-4, zhu2024effectivenessandsafety pages 1-2)
Practical management note	Treat-to-target monitoring uses symptoms plus normalization of inflammatory markers; very mild/episodic FCAS may sometimes be managed with individualized/on-demand IL-1 blockade, but continuous therapy is typical for sustained control and complication prevention (ontario2022…ofthe pages 23-26, ontario2022…ofthe pages 18-20)

Table: This table condenses disease-definition, genetics, phenotype, diagnostics, epidemiology, and treatment evidence for Familial Cold Autoinflammatory Syndrome within the CAPS spectrum. It is designed for rapid knowledge-base population with recent cohort and established trial outcome data.

1. Disease information

1.1. Definition and overview

CAPS is historically described as a clinical spectrum comprising FCAS, Muckle–Wells syndrome (MWS), and CINCA/NOMID, and is now frequently grouped as NLRP3-associated autoinflammatory disease (NLRP3-AID). The shared mechanism is heterozygous gain-of-function NLRP3 variants causing overactivation of the cryopyrin inflammasome and downstream IL-1–mediated inflammation. (meertens2024theriddleof pages 7-8, moltrasio2022nlrp3inflammasomeand pages 1-2)

A foundational historical description highlighted multigenerational families with recurrent, cold-triggered episodes including “urticarial-like rash, limb pain, fever, and transient joint stiffness,” resistant to standard allergic urticaria therapies. (putnam2024thediscoveryof pages 1-3)

1.2. Key identifiers (with availability caveat)

MONDO: familial cold autoinflammatory syndrome = MONDO_0018768 (Open Targets disease mapping). (OpenTargets Search: Familial cold autoinflammatory syndrome,Cryopyrin-associated periodic syndrome)
MONDO subtype concept: familial cold autoinflammatory syndrome 1 = MONDO_0007349. (OpenTargets Search: Familial cold autoinflammatory syndrome,Cryopyrin-associated periodic syndrome)

Evidence for OMIM/Orphanet/ICD/MeSH numeric identifiers was not captured in the retrieved full-text corpus; therefore those identifiers are not asserted here.

1.3. Synonyms / alternative names

Common names used in recent literature include: * Familial Cold Autoinflammatory Syndrome (FCAS) (meertens2024theriddleof pages 7-8) * Familial cold urticaria / familial cold-induced autoinflammatory syndrome (terminology used variably in the CAPS literature) (OpenTargets Search: Familial cold autoinflammatory syndrome,Cryopyrin-associated periodic syndrome, putnam2024thediscoveryof pages 1-3) * Cryopyrin-associated periodic syndromes (CAPS) / cryopyrinopathy (putnam2024thediscoveryof pages 1-3, moltrasio2022nlrp3inflammasomeand pages 1-2) * NLRP3-associated autoinflammatory disease (NLRP3-AID) (meertens2024theriddleof pages 7-8, yun2024geneticvariationsin pages 1-2)

1.4. Evidence sources (aggregated vs individual)

The understanding summarized here comes from: (i) aggregated disease reviews and registry-based analyses (e.g., Eurofever registry ocular statistics), (ii) clinical cohort studies including a 2024 real-world canakinumab cohort, and (iii) clinical trials registered on ClinicalTrials.gov. (zhu2024effectivenessandsafety pages 1-2, fonollosa2024updateonocular pages 4-6, NCT00685373 chunk 1, NCT00288704 chunk 2)

2. Etiology

2.1. Disease causal factors

Primary causal factor (most common FCAS/CAPS form): * Genetic—heterozygous gain-of-function (GOF) variants in NLRP3 cause constitutive inflammasome hyperactivation, increasing caspase-1 activity and overproduction of IL-1β (and IL-18), producing systemic sterile inflammation. (donato2021monogenicautoinflammatorydiseases pages 13-14, putnam2024thediscoveryof pages 1-3, moltrasio2022nlrp3inflammasomeand pages 1-2)

Other genetic contributors and diagnostic pitfalls: * Somatic mosaic NLRP3 mutations can cause CAPS phenotypes and may be missed by standard sequencing; deep sequencing may be required. (alehashemi2020humanautoinflammatorydiseases pages 3-5, delplanque2023diagnosticandtherapeutic pages 5-9) * CAPS-like phenotypes can arise from other genes (e.g., NLRP12, NLRC4, PLCG2 in FCAS-like entities), motivating broader gene panel testing in mutation-negative cases. (donato2021monogenicautoinflammatorydiseases pages 13-14, OpenTargets Search: Familial cold autoinflammatory syndrome,Cryopyrin-associated periodic syndrome)

Abstract quote (mechanistic framing): A 2024 Immunological Reviews article summarizes current understanding as: “the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity…[driving] downstream inflammation mediated by IL-1 and IL-18.” (Putnam et al., 2024-12, https://doi.org/10.1111/imr.13292) (putnam2024thediscoveryof pages 1-3)

2.2. Risk factors

Cold exposure is a characteristic trigger for FCAS attacks (“generalized cold exposure” described as pathognomonic in FCAS-focused pediatric review material). (meertens2024theriddleof pages 7-8, ontario2022…ofthe pages 15-18)
Family history consistent with autosomal dominant inheritance is a key clinical risk indicator for NLRP3-AID (CAPS). (delplanque2023diagnosticandtherapeutic pages 1-5)

2.3. Protective factors

No protective genetic variants or protective environmental factors were identified in the retrieved evidence corpus.

2.4. Gene–environment interaction

The dominant gene–environment interaction in FCAS is NLRP3 pathway dysregulation + cold exposure, where cold acts as an environmental trigger of inflammatory flares in genetically predisposed individuals. (meertens2024theriddleof pages 7-8)

3. Phenotypes

3.1. Core FCAS/CAPS phenotype set

Across CAPS and specifically in FCAS, commonly reported manifestations include: * Urticarial-like rash (often neutrophilic) (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 1-3) * Low-grade fever during attacks (meertens2024theriddleof pages 7-8) * Arthralgia / myalgia; transient joint stiffness (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 1-3) * Ocular inflammation including conjunctivitis/red eye (can include episcleritis/uveitis in broader CAPS) (meertens2024theriddleof pages 7-8, fonollosa2024updateonocular pages 6-7)

Trigger and timing: FCAS is “classically triggered by generalized cold exposure,” with symptoms described as potentially worse later in the day after exposure. (meertens2024theriddleof pages 7-8)

3.2. Severe-spectrum CAPS features (contextual for differential / progression)

More severe CAPS phenotypes (MWS, NOMID/CINCA) can include: * Sensorineural hearing loss (notably in MWS and severe phenotypes) (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 3-4) * AA amyloidosis, including renal involvement/end-stage renal disease in adult life (putnam2024thediscoveryof pages 3-4) * CNS involvement (chronic sterile meningitis, raised intracranial pressure, developmental delay, seizures) (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 3-4)

3.3. Phenotype frequencies / statistics (recent aggregated data)

Ocular involvement: * Eye involvement reported in 71% of CAPS cases in the Eurofever registry. (fonollosa2024updateonocular pages 4-6) * Specific ocular lesion frequencies reported in a 2024 ophthalmology review: conjunctivitis ~62%, uveitis ~28% (mainly anterior), papillitis/papilledema ~27%, keratitis ~10.6%. (Fonollosa et al., 2024-02, https://doi.org/10.3389/fopht.2024.1337329) (fonollosa2024updateonocular pages 6-7)

Long-term complication risk: * A 2021 review reports AA amyloidosis risk in MWS of ~25% (noting historical/untreated risk). (donato2021monogenicautoinflammatorydiseases pages 13-14)

3.4. Suggested HPO terms (examples)

(Exact HPO IDs were not retrieved in the evidence corpus; suggested terms are provided as names.) * Urticarial rash (HP: Urticaria/urticarial eruption) * Fever (HP: Fever) * Arthralgia (HP: Arthralgia) * Myalgia (HP: Myalgia) * Conjunctivitis / Red eye (HP: Conjunctivitis) * Sensorineural hearing impairment (HP: Sensorineural hearing impairment) * AA amyloidosis / renal amyloidosis (HP: Amyloidosis; HP: Proteinuria) * Aseptic meningitis (HP: Aseptic meningitis)

3.5. Quality of life impact

A 2022 review notes that targeted biologics for hereditary systemic autoinflammatory diseases “improves health-related quality of lives and support patients to pursue almost a normal life” in the era of cytokine-targeted therapies. (cinar2022hereditarysystemicautoinflammatory pages 5-7)

4. Genetic / molecular information

4.1. Causal genes

NLRP3 (cryopyrin) is the principal causal gene for FCAS/CAPS, with GOF variants leading to constitutive inflammasome activation. (meertens2024theriddleof pages 7-8, moltrasio2022nlrp3inflammasomeand pages 1-2)

4.2. Pathogenic variants and variant characteristics

Reviews report >200 to >250 NLRP3 variants with genotype–phenotype correlations; most pathogenic changes are autosomal dominant missense variants and many cluster in exon 3 in classic descriptions. (donato2021monogenicautoinflammatorydiseases pages 13-14, putnam2024thediscoveryof pages 3-4)
Variant examples linked to milder neurologic involvement vs more severe early onset/hearing loss are described in a 2021 review (e.g., A439V/V198M/E311K; T348M associated with early onset and hearing loss). (donato2021monogenicautoinflammatorydiseases pages 13-14)
Somatic mosaicism: reported to occur in a minority (reviewed range 0.5–19%) and can explain mutation-negative patients. (donato2021monogenicautoinflammatorydiseases pages 13-14)

Allele frequency / population frequency: specific gnomAD-like frequencies were not extracted from the retrieved corpus; however, adult cohort comparison work supports that variants seen in symptomatic cohorts are absent or lower frequency in large controls. (yun2024geneticvariationsin pages 1-2)

4.3. Inheritance

Autosomal dominant inheritance is emphasized for NLRP3-AID (CAPS) and NLRP12-AID. (yun2024geneticvariationsin pages 1-2)

4.4. Modifier genes / protective variants

Not identified in the retrieved evidence.

4.5. Epigenetic information

Epigenetic regulation of NLRP3 is discussed broadly in inflammasome literature, but FCAS-specific epigenetic findings were not extracted in the retrieved evidence corpus.

5. Mechanism / pathophysiology

5.1. Causal chain (trigger → molecular events → clinical manifestations)

Upstream: NLRP3 GOF variants lower the activation threshold and/or cause spontaneous inflammasome assembly. (moltrasio2022nlrp3inflammasomeand pages 1-2)

Inflammasome activation: NLRP3 functions as an intracellular sensor that assembles an inflammasome complex, leading to caspase-1 activation, maturation of IL-1β and IL-18, and inflammatory cell-death pathways (pyroptosis). (putnam2024thediscoveryof pages 1-3, moltrasio2022nlrp3inflammasomeand pages 1-2)

Downstream: Excess IL-1 signaling drives systemic sterile inflammation that manifests clinically as rash, fever, musculoskeletal pain, and organ-specific inflammation (eye, cochlea, CNS) depending on phenotype severity. (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 3-4)

5.2. Visual evidence (pathway and spectrum)

A schematic of the two-signal NLRP3 activation model and a CAPS spectrum comparison table were retrieved from Moltrasio et al. (2022). (moltrasio2022nlrp3inflammasomeand media 827f1c62, moltrasio2022nlrp3inflammasomeand media 6ae99acf)

5.3. Immune system involvement and cell types

The disease is characterized as an innate immune dysregulation disorder (autoinflammatory), with NLRP3 inflammasome signaling as a central regulator. (putnam2024thediscoveryof pages 1-3, delplanque2023diagnosticandtherapeutic pages 1-5)

Suggested Cell Ontology (CL) terms (examples; IDs not retrieved in evidence corpus): * Monocyte * Macrophage * Neutrophil * Dendritic cell

5.4. Suggested GO biological process terms (examples)

Inflammasome complex assembly
Interleukin-1 beta production
Interleukin-18 production
Pyroptosis
Regulation of innate immune response

5.5. Model systems and translational evidence

Concordant results across “clinical studies in CAPS patients,” “ex vivo studies of human cells,” and “in vivo murine models” are highlighted in the 2024 Immunological Reviews synthesis of NLRP3/CAPS discovery and function. (putnam2024thediscoveryof pages 1-3)

6. Anatomical structures affected

6.1. Primary organs and systems

Skin (urticarial-like rash) (meertens2024theriddleof pages 7-8)
Eyes (conjunctivitis, uveitis, papilledema/papillitis, keratitis) (fonollosa2024updateonocular pages 6-7)
Joints / musculoskeletal system (arthralgia, myalgia; more severe: deforming arthropathy) (meertens2024theriddleof pages 7-8, putnam2024thediscoveryof pages 3-4)

6.2. Secondary organ involvement / complications (spectrum-dependent)

Inner ear/cochlea (sensorineural hearing loss) (putnam2024thediscoveryof pages 3-4)
Kidney via AA amyloidosis (especially in MWS; can progress to end-stage renal disease) (putnam2024thediscoveryof pages 3-4)
Central nervous system (aseptic meningitis, seizures, developmental issues in severe phenotypes) (meertens2024theriddleof pages 7-8)

6.3. Suggested UBERON terms (examples)

Skin
Eye
Cochlea / inner ear
Kidney
Brain / meninges

7. Temporal development

7.1. Onset

In a recent CAPS cohort treated with canakinumab, median age at disease onset was reported in days (median 2.5 days), reflecting that CAPS can present extremely early; however, this reflects mixed CAPS phenotypes (predominantly CINCA/NOMID) rather than isolated FCAS. (zhu2024effectivenessandsafety pages 1-2)

7.2. Disease course

FCAS is described as cold-triggered with self-limited episodes compared to more severe CAPS phenotypes; MWS flares are described as lasting 1–2 days in an ocular-focused review. (fonollosa2024updateonocular pages 4-6)

8. Inheritance and population

8.1. Epidemiology

A pediatric autoinflammatory review reports combined CAPS prevalence of approximately 1/360,000. (meertens2024theriddleof pages 7-8)

8.2. Adult-onset/late recognition (real-world diagnostic delay)

An adult cohort study (retrospective; largely Caucasian; 82% women) reports median age at diagnosis 41 ± 23 years and disease duration at diagnosis 14 ± 13 years in adults with NLRP3-AID and/or NLRP12-AID variants after extensive negative autoimmune workups, highlighting that adult recognition may be delayed. (Yun et al., 2024-01, https://doi.org/10.3389/fimmu.2023.1321370) (yun2024geneticvariationsin pages 1-2)

8.3. Penetrance/expressivity

Variable expressivity and genotype–phenotype correlations across NLRP3 variants are emphasized in reviews; explicit penetrance estimates were not extracted from the retrieved evidence corpus. (donato2021monogenicautoinflammatorydiseases pages 13-14, putnam2024thediscoveryof pages 3-4)

9. Diagnostics

9.1. Clinical criteria and diagnostic approach

Diagnosis/classification is based on: 1) compatible clinical phenotype, 2) systemic inflammation markers, and 3) genetic testing where possible.

Inflammation markers: Raised acute phase reactants—especially CRP and SAA—are emphasized as supporting diagnosis and monitoring. (meertens2024theriddleof pages 7-8, ontario2022…ofthe pages 18-20)

Classification thresholds (example): A pediatric review summarizes criteria such that elevated CRP/SAA plus ≥2 clinical features can classify NLRP3-AID even without genetic confirmation; if a pathogenic/likely pathogenic NLRP3 variant is present, only one key sign (urticarial rash, red eye, or neurosensorial hearing loss) may suffice for classification. (meertens2024theriddleof pages 7-8)

Genetic testing strategy: In adults, reviews stress that somatic mosaic NLRP3 mutations (notably in CINCA/NOMID) can be missed by Sanger; massive-parallel sequencing (panels/WES/WGS) is recommended. (delplanque2023diagnosticandtherapeutic pages 5-9)

9.2. Differential diagnosis

Mimics and nearby entities include other monogenic autoinflammatory diseases (e.g., TRAPS, MKD, DIRA; NLRP12-AID) and non-genetic conditions (systemic JIA/Still’s disease, infections, neoplasms, autoimmune diseases). (ontario2022…ofthe pages 13-15, delplanque2023diagnosticandtherapeutic pages 1-5)

A practical clue highlighted in an IL-1-mediated disease review is that FCAS often has a negative ice-cube test, helping distinguish it from acquired cold urticaria. (ontario2022…ofthe pages 15-18)

10. Outcome / prognosis

10.1. Major complications (untreated or undertreated)

AA amyloidosis and renal failure can occur (especially MWS) (putnam2024thediscoveryof pages 3-4)
Sensorineural hearing loss (putnam2024thediscoveryof pages 3-4)
Irreversible ocular and neurologic sequelae risk in NOMID/CINCA (fonollosa2024updateonocular pages 4-6)

10.2. Prognostic impact of modern therapy

Targeted IL-1 blockade is linked to sustained remission, normalization of inflammatory markers (including SAA), and presumed reduction in long-term complications such as amyloidosis by controlling chronic inflammation. (cinar2022hereditarysystemicautoinflammatory pages 5-7)

11. Treatment

11.1. Standard pharmacotherapy (real-world implementation)

IL-1 pathway blockade is the cornerstone of CAPS/FCAS therapy, using: * Anakinra (IL-1 receptor antagonist; blocks IL-1α and IL-1β; daily) (moltrasio2022nlrp3inflammasomeand pages 11-13) * Rilonacept (IL-1 trap; weekly) (moltrasio2022nlrp3inflammasomeand pages 11-13) * Canakinumab (anti–IL-1β monoclonal antibody; every 4–8 weeks) (moltrasio2022nlrp3inflammasomeand pages 11-13, cinar2022hereditarysystemicautoinflammatory pages 5-7)

A treat-to-target approach is described: symptom control plus normalization of inflammatory markers; dosing may require individualization (e.g., more frequent dosing in severe disease/children). (ontario2022…ofthe pages 23-26)

11.2. Evidence of effectiveness (key statistics)

Canakinumab * Trial evidence summarized in a pediatric therapeutics review: at week 24, all canakinumab-treated patients remained in remission vs 25% in placebo. (cinar2022hereditarysystemicautoinflammatory pages 5-7) * Larger cohort evidence summarized in a mechanistic review: 78% persistent clinical remission in a cohort of 166 CAPS patients with no organ-damage progression. (moltrasio2022nlrp3inflammasomeand pages 11-13) * 2024 real-world cohort (China, 10 CAPS patients including 1 FCAS) treated March 2021–Feb 2024: 60% (6/10) complete remission without relapse; ~80% improved fever/rash; 30% required dose escalation; steroid-sparing effect (prednisone use decreased); most common adverse event infection 40%; no serious adverse events. (Zhu et al., 2024-09, https://doi.org/10.1186/s12969-024-01023-w) (zhu2024effectivenessandsafety pages 1-2)

Rilonacept * A review summarizes a randomized trial where rilonacept reduced flares/symptoms in 84% of treated FCAS/MWS patients versus placebo, with sustained response up to two years. (moltrasio2022nlrp3inflammasomeand pages 11-13) * ClinicalTrials.gov details for the phase 3 rilonacept trial define the Key Symptom Score and flare days (e.g., flare day mean KSS >3) and include inflammatory biomarkers CRP and SAA. (NCT00288704, ClinicalTrials.gov) (NCT00288704 chunk 2)

Anakinra * Observational cohorts summarized report complete/partial remission in the range 40–100%, with sustained remission described over multi-year follow-up in severe CAPS cohorts; anakinra is also used when broader IL-1α/β blockade is desired. (moltrasio2022nlrp3inflammasomeand pages 11-13, ontario2022…ofthe pages 23-26)

11.3. Adverse events and safety

An IL-1 inhibitor safety profile in CAPS is generally described as favorable in reviews, with infections and injection-site reactions commonly monitored; the 2024 Chinese cohort reported infection as the most common adverse event (40%) without serious adverse events. (zhu2024effectivenessandsafety pages 1-2, NCT00685373 chunk 1)

11.4. Clinical trials (selected; real-world linkage)

Canakinumab (ACZ885) * NCT00685373 (Novartis): open-label long-term safety/efficacy study in CAPS (FCAS/MWS/NOMID), n=166, age ≥3; primary endpoints include AEs/SAEs/infections/injection-site reactions; secondary includes % without relapse defined using CRP/SAA thresholds and clinical assessments; dosing every 8 weeks with uptitration allowed. (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT00685373) (NCT00685373 chunk 1) * NCT00991146 (Japan): 24-week canakinumab study with extension; registry cites results publication (PMID 23380020). (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT00991146) (NCT00991146 chunk 2)

Rilonacept * NCT00288704: phase 3 trial in FCAS/MWS with defined symptom scoring and biomarkers CRP/SAA; includes adult and pediatric extension elements. (ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT00288704) (NCT00288704 chunk 2)

11.5. Suggested MAXO terms (examples)

(Exact MAXO IDs were not retrieved in the evidence corpus; suggested action terms are provided as names.) * Interleukin-1 inhibition therapy * Monoclonal antibody therapy (anti–IL-1β) * Cytokine receptor antagonist therapy * Anti-inflammatory therapy * Long-term disease monitoring (treat-to-target using inflammatory markers)

12. Prevention

Primary prevention is not currently established for a Mendelian autosomal dominant disorder. The most actionable prevention in practice is tertiary prevention (preventing complications) via early recognition, genetic confirmation when possible, and sustained inflammation suppression (e.g., IL-1 blockade) to reduce risks such as AA amyloidosis and organ damage. (cinar2022hereditarysystemicautoinflammatory pages 5-7, putnam2024thediscoveryof pages 3-4)

13. Other species / natural disease

No naturally occurring non-human FCAS model evidence was extracted from the retrieved corpus.

14. Model organisms

Murine model work is referenced as part of the translational evidence base supporting NLRP3/CAPS biology, but specific engineered lines and phenotype details were not extracted from the retrieved corpus. (putnam2024thediscoveryof pages 1-3)

Expert synthesis / interpretation (2023–2024 emphasis)

Recent (2023–2024) clinical literature emphasizes two practical shifts: (i) diagnostic strategy now explicitly anticipates somatic mosaicism and thus favors deep next-generation sequencing approaches for NLRP3, especially in severe/atypical cases, and (ii) IL-1–targeted biologics remain standard-of-care with growing real-world datasets supporting sustained control and steroid sparing. (delplanque2023diagnosticandtherapeutic pages 5-9, zhu2024effectivenessandsafety pages 1-2)

A 2024 pediatric review also underscores that clinical classification can proceed even when genetic testing is inconclusive by combining elevated CRP/SAA with a small number of high-specificity clinical features, reflecting current pragmatic practice. (meertens2024theriddleof pages 7-8)

URLs and publication dates (key sources cited)

Putnam CD, Broderick L, Hoffman HM. Immunological Reviews. 2024-12. https://doi.org/10.1111/imr.13292 (putnam2024thediscoveryof pages 1-3)
Meertens B et al. Frontiers in Pediatrics. 2024-11. https://doi.org/10.3389/fped.2024.1448176 (meertens2024theriddleof pages 7-8)
Delplanque M et al. Rheumatology. 2023-12. https://doi.org/10.1093/rheumatology/keac712 (delplanque2023diagnosticandtherapeutic pages 1-5)
Fonollosa A et al. Frontiers in Ophthalmology. 2024-02. https://doi.org/10.3389/fopht.2024.1337329 (fonollosa2024updateonocular pages 6-7)
Zhu X et al. Pediatric Rheumatology. 2024-09. https://doi.org/10.1186/s12969-024-01023-w (zhu2024effectivenessandsafety pages 1-2)
ClinicalTrials.gov: NCT00685373 https://clinicaltrials.gov/study/NCT00685373 (NCT00685373 chunk 1)
ClinicalTrials.gov: NCT00288704 https://clinicaltrials.gov/study/NCT00288704 (NCT00288704 chunk 2)

References

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(putnam2024thediscoveryof pages 3-4): Christopher D. Putnam, Lori Broderick, and Hal M. Hoffman. The discovery of nlrp3 and its function in cryopyrin-associated periodic syndromes and innate immunity. Immunological reviews, 322:259-282, Dec 2024. URL: https://doi.org/10.1111/imr.13292, doi:10.1111/imr.13292. This article has 38 citations and is from a domain leading peer-reviewed journal.
(donato2021monogenicautoinflammatorydiseases pages 13-14): Giulia Di Donato, Debora Mariarita d’Angelo, Luciana Breda, and Francesco Chiarelli. Monogenic autoinflammatory diseases: state of the art and future perspectives. International Journal of Molecular Sciences, 22:6360, Jun 2021. URL: https://doi.org/10.3390/ijms22126360, doi:10.3390/ijms22126360. This article has 61 citations.
(alehashemi2020humanautoinflammatorydiseases pages 3-5): Sara Alehashemi and Raphaela Goldbach-Mansky. 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. Frontiers in Immunology, Aug 2020. URL: https://doi.org/10.3389/fimmu.2020.01840, doi:10.3389/fimmu.2020.01840. This article has 122 citations and is from a peer-reviewed journal.
(delplanque2023diagnosticandtherapeutic pages 5-9): Marion Delplanque, Antoine Fayand, Guilaine Boursier, Gilles Grateau, Léa Savey, and Sophie Georgin-Lavialle. Diagnostic and therapeutic algorithms for monogenic autoinflammatory diseases presenting with recurrent fevers among adults. Rheumatology, 62:2665-2672, Dec 2023. URL: https://doi.org/10.1093/rheumatology/keac712, doi:10.1093/rheumatology/keac712. This article has 26 citations and is from a peer-reviewed journal.
(ontario2022…ofthe pages 15-18): W Ontario. … of the il 1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (caps), tumor necrosis factor receptor-associated periodic syndrome (traps …. Unknown journal, 2022.
(fonollosa2024updateonocular pages 4-6): Alex Fonollosa, Ester Carreño, Antonio Vitale, Ankur K. Jindal, Athimalaipet V. Ramanan, Laura Pelegrín, Borja Santos-Zorrozua, Verónica Gómez-Caverzaschi, Luca Cantarini, Claudia Fabiani, and José Hernández-Rodríguez. Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases. Frontiers in Ophthalmology, Feb 2024. URL: https://doi.org/10.3389/fopht.2024.1337329, doi:10.3389/fopht.2024.1337329. This article has 18 citations.
(fonollosa2024updateonocular pages 6-7): Alex Fonollosa, Ester Carreño, Antonio Vitale, Ankur K. Jindal, Athimalaipet V. Ramanan, Laura Pelegrín, Borja Santos-Zorrozua, Verónica Gómez-Caverzaschi, Luca Cantarini, Claudia Fabiani, and José Hernández-Rodríguez. Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases. Frontiers in Ophthalmology, Feb 2024. URL: https://doi.org/10.3389/fopht.2024.1337329, doi:10.3389/fopht.2024.1337329. This article has 18 citations.
(ontario2022…ofthe pages 18-20): W Ontario. … of the il 1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (caps), tumor necrosis factor receptor-associated periodic syndrome (traps …. Unknown journal, 2022.
(ontario2022…ofthe pages 13-15): W Ontario. … of the il 1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (caps), tumor necrosis factor receptor-associated periodic syndrome (traps …. Unknown journal, 2022.
(delplanque2023diagnosticandtherapeutic pages 1-5): Marion Delplanque, Antoine Fayand, Guilaine Boursier, Gilles Grateau, Léa Savey, and Sophie Georgin-Lavialle. Diagnostic and therapeutic algorithms for monogenic autoinflammatory diseases presenting with recurrent fevers among adults. Rheumatology, 62:2665-2672, Dec 2023. URL: https://doi.org/10.1093/rheumatology/keac712, doi:10.1093/rheumatology/keac712. This article has 26 citations and is from a peer-reviewed journal.
(moltrasio2022nlrp3inflammasomeand pages 11-13): Chiara Moltrasio, Maurizio Romagnuolo, and Angelo Valerio Marzano. Nlrp3 inflammasome and nlrp3-related autoinflammatory diseases: from cryopyrin function to targeted therapies. Frontiers in Immunology, Oct 2022. URL: https://doi.org/10.3389/fimmu.2022.1007705, doi:10.3389/fimmu.2022.1007705. This article has 77 citations and is from a peer-reviewed journal.
(cinar2022hereditarysystemicautoinflammatory pages 5-7): Ovgu Kul Cinar, Amber Putland, Karen Wynne, Despina Eleftheriou, and Paul A. Brogan. Hereditary systemic autoinflammatory diseases: therapeutic stratification. Frontiers in Pediatrics, Apr 2022. URL: https://doi.org/10.3389/fped.2022.867679, doi:10.3389/fped.2022.867679. This article has 21 citations.
(ontario2022…ofthe pages 23-26): W Ontario. … of the il 1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (caps), tumor necrosis factor receptor-associated periodic syndrome (traps …. Unknown journal, 2022.
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(zhu2024effectivenessandsafety pages 1-2): Xiaona Zhu, Jiaqi Fan, Yanyan Huang, Yongbin Xu, Zhi Yang, Ruohang Weng, Ying Luo, Jun Yang, and Tingyan He. Effectiveness and safety of canakinumab in cryopyrin-associated periodic syndrome: a retrospective study in china. Pediatric Rheumatology, Sep 2024. URL: https://doi.org/10.1186/s12969-024-01023-w, doi:10.1186/s12969-024-01023-w. This article has 5 citations and is from a peer-reviewed journal.
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(NCT00685373 chunk 1): 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. Novartis. 2008. ClinicalTrials.gov Identifier: NCT00685373
(NCT00288704 chunk 2): Rilonacept for Treatment of Cryopyrin-Associated Periodic Syndromes (CAPS). Regeneron Pharmaceuticals. 2005. ClinicalTrials.gov Identifier: NCT00288704
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(moltrasio2022nlrp3inflammasomeand media 6ae99acf): Chiara Moltrasio, Maurizio Romagnuolo, and Angelo Valerio Marzano. Nlrp3 inflammasome and nlrp3-related autoinflammatory diseases: from cryopyrin function to targeted therapies. Frontiers in Immunology, Oct 2022. URL: https://doi.org/10.3389/fimmu.2022.1007705, doi:10.3389/fimmu.2022.1007705. This article has 77 citations and is from a peer-reviewed journal.
(NCT00991146 chunk 2): 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. Novartis Pharmaceuticals. 2009. ClinicalTrials.gov Identifier: NCT00991146

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Classifications

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Comprehensive Disease Characteristics Report: Familial Cold Autoinflammatory Syndrome (FCAS)

Executive summary

1. Disease information

1.1. Definition and overview

1.2. Key identifiers (with availability caveat)

1.3. Synonyms / alternative names

1.4. Evidence sources (aggregated vs individual)

2. Etiology

2.1. Disease causal factors

2.2. Risk factors

2.3. Protective factors

2.4. Gene–environment interaction

3. Phenotypes

3.1. Core FCAS/CAPS phenotype set

3.2. Severe-spectrum CAPS features (contextual for differential / progression)

3.3. Phenotype frequencies / statistics (recent aggregated data)

3.4. Suggested HPO terms (examples)

3.5. Quality of life impact

4. Genetic / molecular information

4.1. Causal genes

4.2. Pathogenic variants and variant characteristics

4.3. Inheritance

4.4. Modifier genes / protective variants

4.5. Epigenetic information

5. Mechanism / pathophysiology

5.1. Causal chain (trigger → molecular events → clinical manifestations)

5.2. Visual evidence (pathway and spectrum)

5.3. Immune system involvement and cell types

5.4. Suggested GO biological process terms (examples)

5.5. Model systems and translational evidence

6. Anatomical structures affected

6.1. Primary organs and systems

6.2. Secondary organ involvement / complications (spectrum-dependent)

6.3. Suggested UBERON terms (examples)

7. Temporal development

7.1. Onset

7.2. Disease course

8. Inheritance and population

8.1. Epidemiology

8.2. Adult-onset/late recognition (real-world diagnostic delay)

8.3. Penetrance/expressivity

9. Diagnostics

9.1. Clinical criteria and diagnostic approach

9.2. Differential diagnosis

10. Outcome / prognosis