Cold-Induced Urticarias with Familial Background: Clinical Spectrum, Pathogenesis, and Diagnostic Challenges

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.