Definition and genetics
Familial cold autoinflammatory syndrome (FCAS) is the mildest of the cryopyrin-associated periodic syndromes (CAPS), a spectrum of monogenic autoinflammatory diseases caused by gain-of-function mutations in NLRP3 (formerly CIAS1; chromosome 1q44), which encodes cryopyrin. Inheritance is autosomal dominant (de novo mutations and somatic mosaicism also occur). Mutant cryopyrin produces constitutive activation of the NLRP3 inflammasome, with uncontrolled caspase-1 activation and IL-1β oversecretion. CAPS forms a clinical continuum of increasing severity: FCAS (mild, cold-triggered) → Muckle-Wells syndrome (sensorineural hearing loss, amyloidosis) → neonatal-onset multisystem inflammatory disease (NOMID/CINCA) (severe, with CNS and bone involvement). FCAS occurs across ethnicities.
Episode pattern
The defining trigger is generalised cold exposure (ambient cold, air conditioning, cold weather), with symptoms typically beginning 1–2 hours after exposure. Attacks are short — most last under 24 hours. Onset is in early infancy, characteristically before 6 months of age. The tight, reproducible link between environmental cooling and attacks is the central diagnostic feature and distinguishes FCAS from FMF, TRAPS, and HIDS. Because the cold trigger may be subtle (a cold room, a swimming pool, an evening drop in temperature), a careful exposure history is often what unlocks the diagnosis.
Clinical features
A cold-provoked attack combines low-grade fever, a cold-induced urticaria-like (neutrophilic) rash, arthralgia of the extremities, and conjunctivitis. Profuse sweating, drowsiness, headache, nausea, and extreme thirst may accompany attacks. By definition FCAS lacks the features that mark more severe CAPS — sensorineural deafness, periorbital oedema, lymphadenopathy, and serositis are absent. Acute-phase reactants rise during attacks; in more active disease, low-grade inflammation may persist between episodes.
Diagnosis
Diagnosis is clinical — a cold-triggered urticarial-febrile syndrome from infancy with autosomal dominant inheritance — confirmed by NLRP3 sequencing (note that somatic mosaicism may be missed on standard germline testing and warrants deep sequencing when suspicion is high). The 2019 Eurofever/PRINTO classification criteria combine genetic and clinical variables to classify CAPS and separate it from the other hereditary recurrent fevers.
See the full criteria: FCAS Syndrome
Red flags
- AA (secondary) amyloidosis — uncommon in pure FCAS but a defining risk as the phenotype shades toward Muckle-Wells/NOMID; monitor inter-attack acute-phase reactants and screen for proteinuria.
- Sensorineural hearing loss, chronic aseptic meningitis, papilloedema, or epiphyseal overgrowth — signal the more severe end of the CAPS spectrum and mandate audiology, ophthalmology, and neuroimaging.
- Onset in the neonatal period with persistent (non-cold-dependent) inflammation — reconsider NOMID/CINCA.
Management overview
Mild, infrequent FCAS may be managed by cold avoidance alone. For frequent or disabling disease — and for all more severe CAPS phenotypes to prevent end-organ damage — IL-1 blockade is highly effective and is the mainstay (e.g. canakinumab, anakinra, rilonacept), often producing dramatic and sustained control. Early, sustained IL-1 suppression in the severe phenotypes aims to prevent deafness, amyloidosis, and CNS sequelae. (Therapeutic classes only — confirm agent, dose, and monitoring against current formularies.)
References
- Gattorno M, et al. Ann Rheum Dis. 2019;78:1025–1032 (Eurofever/PRINTO).
- Hoffman HM, et al. J Allergy Clin Immunol. 2001;108:615–620.
- ter Haar NM, et al. Ann Rheum Dis. 2015;74:1636–1644 (SHARE).
- Nelson Textbook of Pediatrics, 21st ed.
Decision support for qualified clinicians only — verify against current primary guidelines and your clinical judgement.