Familial cold inflammatory syndrome 1 L50.2

Kile and Rusk (1940) first described familial cold urticaria. The proband in their family developed urticarial wheals, pain and swelling of the joints, chills, and fever after cold exposure. Witherspoon et al (1948) also described familial urticaria after cold exposure.

Cold-induced autoinflammatory syndrome, familial form 1, also known as FCAS1, is a hereditary autoinflammatory syndrome caused by a heterozygous mutation in the NLRP3 gene (1q44).

The clinical picture of FACS1 used to be subsumed under the term "cold urticaria" in the past, unlike other entities in this family. This group of diseases has since been classified as hereditary periodic fever syndromes. All entities are characterized by cold-provoked itchy, burning or slightly painful exanthema (usually limited to the contact site), which can be accompanied by fever attacks and other signs of inflammation.

So far, 4 genotypes with only slightly different phenotypes (see heterogeneity below) have been described, which are now referred to as "cold-induced autoinflammatory syndromes, familial form 1-4" (FACS1-4). The following genotypic variants belong to this family:

• Familial cold-induced autoinflammatory syndrome 1 (FCAS1; mutations in the NLRP3 gene).
• Familial cold-inducedautoinflammatory syndrome 2(FCAS2; OMIM: 609648; heterozygous mutations in the NLRP12 gene)
• Familial cold-induced autoinflammatory syndrome3(FCAS3; mutations in the PLCG2 gene)
• Familial cold-induced autoinflammatory syndrome 4(FCAS4; mutations in the NLRC4 gene).

FCAS1 is clinically characterized by recurrent episodes (with repeated exposure) of urticarial exanthema, which are accompanied by arthralgias, myalgias, fever and chills as well as swelling of the extremities after exposure to cold. In rare cases, renal amyloidosis can also develop as a complication after decades of progression (Hoffman et al. 2000).

The overlapping CAPS syndromes, which are also all caused by a mutation in the NLRP3 gene, include:

• Muckle-Wells syndrome (CAPS2; 191900), which has a high incidence of amyloidosis and late-onset sensorineural deafness
• and
• Chronic neurological cutaneous and articular syndrome (CINCA, CAPS3; 607115), which has an earlier onset and a more severe phenotype.

Acquired cold urticaria: In FACS1, the duration of attacks is significantly longer than in acquired cold urticaria. The lesions in FACS1 are erythematous rather than urticarial and are accompanied by fever, chills, arthralgia and stiffness of the joints. Leukocytosis is often present. Leukocytosis is absent in the acquired form (Zip et al.1993).

Muckle-Wells syndrome: By analyzing 5 families with familial cold urticaria, Hoffman et al. (2000) identified a linkage to 1q44. The authors hypothesized that familial cold urticaria and Muckle-Wells syndrome are caused by allelic disorders.

Based on the genetic evidence and the phenotypic similarity with hereditary periodic fever syndromes (e.g. familial Mediterranean fever/ 249100), Hoffman et al. (2001) proposed the term "familial cold autoinflammatory syndrome" for the disease previously referred to as"familial cold urticaria ".

Doeglas (1973) reported a large kindred with 10 affected individuals. One patient developed leukocytosis after the onset of exanthema.

Ormerod et al (1993) studied 8 of 20 affected members of a 46-member family. Urticaria usually did not appear until early adulthood.

Zip et al (1993) reported a large and extensively affected family. They found reports of 10 pedigrees, 7 from the United States and one each from Holland, France, and South Africa. In their own family, the disease was passed through 6 generations and consequently through 8 generations. The onset of the disease was in infancy. The onset of urticarial symptoms occurred half an hour to 6 hours after exposure to cold.

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