Familial cold urticaria L50.2

A rare family of diseases belonging to the hereditary periodic fever syndromes, with cold-provoked itchy, burning or slightly painful exanthemas (usually limited to the site of contact) accompanied by episodes of fever and other signs of inflammation. So far, 3 genotypes with slightly different phenotypes have been described under the name "cold-induced autoinflammatory syndromes, familial form 1-4":

1. "Cold-induced autoinflammatory syndrome, familial " (FCAS1) is a hereditary autoinflammatory syndrome caused by a heterozygous mutation in the NLRP3 gene (1q44). FCAS1 is clinically characterized by recurrent episodes (with repeated exposure) of urticarial exanthema associated with arthralgias, myalgias, fever and chills, and swelling of the extremities after exposure to cold. After decades of progression, in rare cases patients may also develop late-onset renal amyloidosis (Hoffman et al. 2000).
2. "Cold-induced autoinflammatory syndrome 2, familial" (FCAS2; OMIM: 609648). Autosomal dominant syndrome 2 is caused by heterozygous mutations in the NLRP12 gene on chromosome 19q13.42.
3. The autosomal-dominantly inherited"Cold-induced autoinflammatory syndrome 3, familial" (FCAS3), also called PLCG2-associated antibody deficiency and immune dysregulation (PLAID) is caused by heterozygous deletions in the PLCG2 gene on chromosome 16q23.
4. " Cold-induced autoinflammatory syndrome 4, familial " FCAS4 for short, is associated with a heterozygous mutation in the NLRC4 gene (606831) on chromosome 2p22.

Our understanding of the mechanisms by which cells sense subnormal temperature and initiate inflammatory responses is still limited. It is conceivable that the mutations underlying FCAS have led to misfolded proteins that are recognized by the temperature-sensitive chaperone HSC70 (HSPA8). At 37 °C, HSC70 would interact with the mutant proteins and keep them inactive. Lowered temperatures could lead to a loss of this interaction due to a conformational change of HSC70. Have HSC70 as a cold sensor in various pathological conditions where symptoms worsen at low temperatures (Raghawan AK et al. (2011).

1. Aganna E (2002) Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 46: 2445-2452
2. Hoffman HM et al (2001) Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 108: 615-620.
3. Johnstone RF et al (2003) A large kindred with familial cold autoinflammatory syndrome. Ann Allergy Asthma Immunol 90: 233-237.
4. Kile RL, Rusk HA (1940) A case of cold urticaria with unusual family history. JAMA 114: 1067-1068
5. Raghawan AK et al. (2011) HSC70 as a sensor of low temperature: role in cold-triggered autoinflammatory disorders.The FEBS Journal https://doi.org/10.1111/febs.16203