Background: Familial cold urticarias (FCU) are a group of rare hereditary disorders triggered by exposure to low temperatures. Their pathogenesis is complex, involving mast cell activation, inflammasome dysregulation, and abnormalities of the kallikrein-kinin system. This review aims to summarize the genetic classification, molecular mechanisms, and clinical implications of FCU in diagnosis and management. Methods: Recent literature was reviewed to outline the clinical and molecular characteristics of familial atypical cold urticaria (FACU), familial cold autoinflammatory syndromes (FCAS; including NLRP3-, NLRP12-, NLRC4-, and PLCG2-related subtypes), FXII-associated cold autoinflammatory syndrome (FACAS), and familial predisposed acquired cold urticaria (FP-ACU). Mechanistic clues and diagnostic strategies were analyzed, emphasizing the integration of clinical features with molecular findings. Results: Distinct FCU subtypes exhibit defined genetic bases: gain-of-function mutations in NLRP3, NLRP12, and NLRC4 result in inflammasome hyperactivation; in-frame deletions in PLCG2 lead to temperature-dependent immune signaling dysregulation; and heterozygous F12 variants link contact activation with inflammatory cascades. Combining cold stimulation tests, inflammatory biomarkers, and targeted genetic sequencing enables precise molecular stratification. Conclusions: Molecular subclassification of FCU improves diagnostic accuracy and informs targeted therapy. Future research should focus on the interplay between cold-sensing ion channels, mast cell activation, and inflammasome signaling to advance precision diagnosis and individualized treatment of cold-induced urticarias.

Familial cold inflammatory syndrome (FCAS) is a rare, inherited inflammatory disease characterized by episodes of fever, rash, and arthralgias after exposure to cold stimuli. Previous literature has established FCAS linked to autosomal dominant mutations in the NLRP3 (CIAS1) and NLRP12 genes. Moreover, there has been recent evidence of NLRC4-inflammasomopathies. Although there have been cases of FCAS secondary to missense mutations in NLRC4, we report the first symptomatic case associated with a 93-base-pair in-frame deletion within Exon 5 of the leucine rich repeat domain.

Inflammasomes are supramolecular protein complexes implicated in the detection of pathogens or danger-associated molecules and are responsible for mounting the first line of innate immune response to counteract these signals and restore tissue homeostasis. Among different inflammasomes identified so far, NLRP3 is of main interest since mutations in Nlrp3 gene are associated with autoinflammatory diseases such as Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, and familial cold urticaria/autoinflammatory syndrome. On the other hand, whereas other inflammasomes are mainly detectors of specific molecular motifs, NLRP3 is acting as a general sensor of cellular perturbations including potassium efflux, lysosomal damage, and ROS production. Besides this central role of NLRP3 in inflammation, recent publications show that the NLRP3 inflammasome is also involved in the physiopathology of several neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review gives an overview of the established functions of the NLRP3 inflammasome in mediating inflammation in macrophages and describes its recently discovered roles in neurological disorders in promoting neuroinflammation, as well as modulating key proteins mediating the disorders. Finally, we discuss the targeting of NLRP3 in neurological diseases and present some examples of NLRP3 inhibitors that could be used in neurological disorder treatments.

The auto-inflammatory diseases linked to NLRC4 mutations are recently described entities. Transmission is autosomal dominant in 80 % of cases; cases of somatic mutation have already been reported. The disease may display two very different clinical phenotypes: the phenotype 1 (30 %), severe, is dominated by a multisystemic inflammation starting in the first year of life with symptoms of chronic inflammatory bowel disease (IBD), macrophagic actication syndrome (MAS), or even a presentation suggesting a cryopyrinopathy in its CINCA form; the mortality of this phenotype is high (25 %). The phenotype 2 (70 %), mild, usually starts after the age of 3 and is characterized by cold urticaria, arthralgia, ocular features and fever in 50 % of cases without visceral failure. Anti-interleukin-1 inhibitors are effective in most cases (83 %). Interleukin-18 (IL-18) levels are very high in both clinical forms. Interleukin-18 inhibitors and anti-interferon-gamma inhibitors were remarkably effective in two very severe phenotype 1 patients. Thus, NLRC4 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because very recently described, this group of diseases could be evoked by an internist in front of cold familial urticarial; probably more and more cases will be diagnosed thanks to the major progresses of genetic diagnostic tools such as next generation sequencing.