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

<b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> Distinct FCU subtypes exhibit defined genetic bases: gain-of-function mutations in <i>NLRP3</i>, <i>NLRP12</i>, and <i>NLRC4</i> result in inflammasome hyperactivation; in-frame deletions in <i>PLCG2</i> lead to temperature-dependent immune signaling dysregulation; and heterozygous <i>F12</i> variants link contact activation with inflammatory cascades. Combining cold stimulation tests, inflammatory biomarkers, and targeted genetic sequencing enables precise molecular stratification. <b>Conclusions:</b> 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.