| 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 (pqac-00000002, pqac-00000003, pqac-00000005) |
| 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 (pqac-00000000) |
| Common synonyms | FCAS; familial cold urticaria; familial cold-induced autoinflammatory syndrome; CAPS; cryopyrinopathy; NLRP3-associated autoinflammatory disease / NLRP3-AID (pqac-00000002, pqac-00000003, pqac-00000008) |
| 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 (pqac-00000001, pqac-00000004, pqac-00000021) |
| 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 (pqac-00000002, pqac-00000003, pqac-00000024) |
| 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 (pqac-00000002, pqac-00000015, pqac-00000022) |
| 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 (pqac-00000001, pqac-00000023, pqac-00000028) |
| 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% (pqac-00000022, pqac-00000025) |
| 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 (pqac-00000016, pqac-00000018, pqac-00000021) |
| 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 (pqac-00000015, pqac-00000017, pqac-00000020) |
| 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 (pqac-00000003, pqac-00000005) |
| Epidemiology | Combined CAPS prevalence is reported as approximately **1/360,000**; FCAS is rare and usually begins in infancy/childhood (pqac-00000002) |
| 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 (pqac-00000004, pqac-00000010, pqac-00000011) |
| 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 (pqac-00000010, pqac-00000011) |
| 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 (pqac-00000010) |
| 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 (pqac-00000010, pqac-00000009) |
| 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** (pqac-00000012, pqac-00000014) |
| 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 (pqac-00000009, pqac-00000018) |


*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.*