Cryopyrin-Associated Periodic Syndromes (CAPS) — Familial Cold Urticaria

Cryopyrin-associated periodic syndromes (CAPS) are a spectrum of three autosomal dominant systemic autoinflammatory disorders sharing common molecular cause: heterozygous gain-of-function mutations in NLRP3 gene (formerly CIAS1, chromosome 1q44, encoding cryopyrin/NALP3). NLRP3 is a key component of the NLRP3 inflammasome, a cytosolic multiprotein complex that activates caspase-1 to process pro-IL-1β into mature IL-1β, driving systemic inflammation. Gain-of-function mutations result in constitutive or hyperactive inflammasome, with uncontrolled IL-1β secretion and recurrent or chronic inflammation.

Three classical phenotypes form severity continuum: (1) Familial Cold Autoinflammatory Syndrome (FCAS, formerly Familial Cold Urticaria) — mildest, OMIM 120100, prevalence approximately 1 per million in USA; (2) Muckle-Wells Syndrome (MWS) — intermediate, OMIM 191900, originally described in 1962 by Thomas Muckle and Michael Wells; (3) Neonatal-Onset Multisystem Inflammatory Disease (NOMID/CINCA — Chronic Infantile Neurological Cutaneous and Articular syndrome) — most severe, OMIM 607115. Some patients overlap or transition between phenotypes. CAPS-like presentations may also occur from somatic NLRP3 mosaicism (especially in NOMID — undetectable in routine peripheral blood sequencing, requires deep sequencing of affected tissue or buccal cells).

FCAS clinical features: onset usually <6 months age (often within hours of birth), recurrent attacks 1–2 hours after generalized environmental cold exposure (air conditioning, cool weather, drafts — not direct contact urticaria), urticarial rash (often non-pruritic, more burning), low-grade fever, chills, headache, arthralgia, conjunctivitis, lasting <24 hours, family history of similar episodes (autosomal dominant), no severe systemic complications.

MWS clinical features: chronic or recurrent urticarial rash (not exclusively cold-triggered), recurrent fever and chills, arthralgia of large joints, conjunctivitis, progressive sensorineural hearing loss starting in adolescence-young adulthood (in 50 percent), and serum amyloid A (AA) amyloidosis with renal involvement (proteinuria, nephrotic syndrome, renal failure — 25–40 percent if untreated), gradual onset in early childhood often after preceding 'FCAS-like' phase. NOMID/CINCA clinical features: presents at birth or within first weeks of life with chronic non-itchy urticarial rash, chronic aseptic meningitis with elevated CSF protein, neutrophilic CSF pleocytosis, intracranial hypertension causing papilledema, optic atrophy, ventriculomegaly; sensorineural hearing loss; characteristic skeletal involvement — epiphyseal-metaphyseal overgrowth especially affecting knee (radiographic 'patellar enlargement,' long bone deformity), frontal bossing, saddle nose; cognitive impairment, growth retardation, premature death in untreated patients.