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Familial cold autoinflammatory syndrome (FCAS) is a rare autosomal dominant autoinflammatory disease characterized by cold‐induced urticaria, fever, arthralgia, conjunctivitis, and leukocytosis, typically with onset in infancy or early childhood. Gain-of-function variants in the NLRP3 gene, encoding the cryopyrin protein, underlie FCAS through overactivation of the inflammasome complex and excessive interleukin-1β (IL-1β) release. Clinical presentation overlaps with other cryopyrin‐associated periodic syndromes (CAPS), including Muckle-Wells syndrome and CINCA/NOMID, reflecting a phenotypic continuum tied to variant position and mosaicism.
The association between NLRP3 and FCAS meets a Strong ClinGen validity classification based on: identification of pathogenic variants in at least 12 unrelated families across European, North American, and Asian populations, segregation with disease in multiple multigenerational pedigrees, and concordant functional studies demonstrating inflammasome overactivation (11992256,12522564,15801036).
FCAS is inherited in an autosomal dominant manner with high penetrance. Segregation analysis across seven multigenerational families revealed over 19 affected relatives carrying pathogenic NLRP3 variants (e.g., p.Ala439Thr) (15801036). At least 30 probands have been described with heterozygous missense changes clustering in exon 3 (NACHT domain), including recurrent and founder alleles. A key recurrent variant, c.1316C>T (p.Ala439Val), segregates in two European pedigrees and a Portuguese case, supported by haplotype analysis indicating independent mutational events (31777803).
To date, over 20 missense mutations in NLRP3 are associated with FCAS, with hotspots at residues Val198, Arg260, Asp303, Leu353, and Ala439 (11992256,12522564). Founder effects have been described for the Leu353Pro allele in four North American families, while Ala439Thr and Ala439Val occur in diverse ethnic groups. Somatic mosaicism at these and other sites (e.g., Asp303Ala) further broadens the mutational landscape and influences mosaic phenotypes.
Disease-associated NLRP3 mutants exhibit constitutive ASC speck assembly, enhanced NF-κB activity, and spontaneous IL-1β secretion in monocytic models, effects abolished by ASC knockdown (15020601). Monocytes from patients display rapid cathepsin B–dependent cell death upon inflammasome activation and heightened proinflammatory cytokine release, correlating with clinical flares and confirming gain-of-function pathogenicity.
IL-1 blockade with anakinra or canakinumab yields dramatic and sustained remissions in FCAS patients with confirmed NLRP3 variants, underscoring the direct mechanistic link between inflammasome overactivation and disease (18174231). Genetic testing for NLRP3 exon 3 variants is recommended in suspected cases, including low‐level mosaicism assessments when conventional sequencing is negative.
Key Take-home: Heterozygous gain-of-function NLRP3 variants cause autosomal dominant FCAS via inflammasome hyperactivation and IL-1β overproduction; genetic diagnosis guides effective IL-1–targeted therapy.
Gene–Disease AssociationStrongIdentification of NLRP3 pathogenic variants in ≥12 unrelated families, multi-family segregation, functional concordance Genetic EvidenceStrong
Functional EvidenceModerateMultiple in vitro models show constitutive inflammasome activation and IL-1β overproduction |