Also known as:
- Cold Hypersensitivity
- Cold-Induced Autoinflammatory Syndrome
- Familial Cold Urticaria; (FCU)
- Cryopyrin-Associated Periodic Syndrome 1; (CAPS1)
Familial cold autoinflammatory syndrome (FCAS) is characterized clinically by recurrent attacks of a maculopapular rash associated with arthralgias, myalgias, fever and chills, and swelling of the extremities after exposure to cold. Despite the first description of ‘cold urticaria’ (Kile and Rusk, 1940) the rash in most patients is nonpruritic and nonurticarial. Rarely, some patients may also develop late-onset renal amyloidosis (Hoffman et al., 2000).
Overlapping syndromes also caused by mutation in the NLRP3 gene include Muckle-Wells syndrome (CAPS2; 191900), which has a high frequency of amyloidosis and late-onset sensorineural deafness, and chronic neurologic cutaneous and articular syndrome (CINCA, CAPS3; 607115), which shows earlier onset and a more severe phenotype.
Genetic Heterogeneity of Familial Cold Autoinflammatory Syndrome
See also FCAS2 (611762), caused by mutation in the NLRP12 gene (609648) on chromosome 19q13; FCAS3 (614468), caused by mutation in the PLCG2 gene (600220) on chromosome 16q23; and FCAS4 (616115), caused by mutation in the NLRC4 gene (606831) on chromosome 2p22.
Kile and Rusk (1940) first described familial cold urticaria. The proband in their family developed urticarial wheals, pain and swelling of joints, chills, and fever after exposure to the cold. Witherspoon et al. (1948) also described familial urticaria resulting from cold exposure.
Doeglas (1973) reported a large kindred with 10 affected individuals. One of the 10 had leukocytosis during an attack. Derbes and Coleman (1972) reviewed the literature on familial cold urticaria and described several similar disorders to provide a basis for differential diagnosis.
Ormerod et al. (1993) studied 8 of 20 affected members from a 46-member affected family. Urticaria was maximal in early adult life. Three patients responded favorably to treatment with stanozolol. The authors suggested that this disorder, like hereditary angioedema (HAE; 106100), involves deficiency of an inhibitory factor.
Zip et al. (1993) reported a large and extensively affected family. They found reports of 10 pedigrees, 7 from the United States and 1 each from Holland, France, and South Africa. Their own family showed transmission through 6 generations and by inference 8 generations. The onset of the disorder was in infancy. The onset of symptoms after cold challenge was delayed (one-half to 6 hours).
Zip et al. (1993) tabulated the differences between idiopathic acquired cold urticaria and familial cold urticaria. In the familial form, the lesions tend to be erythematous rather than urticarial and to be accompanied by fever, chills, arthralgias, and stiffness. Leukocytosis is present, whereas it is absent in acquired cold urticaria, duration of the episodes is much longer, passive transfer is negative, and mast cell degranulation is absent.
By analyzing 5 families with familial cold urticaria, Hoffman et al. (2000) identified linkage to 1q44. They found a 2-point maximum lod score of 8.13 at recombination fraction 0.0 for marker D1S2836; multipoint linkage identified a maximum lod score of 10.92 in the same region; and haplotype analysis defined a 10.5-cM region between D1S423 and D1S2682. Hoffman et al. (2000) suggested that familial cold urticaria and Muckle-Wells syndrome are allelic disorders. The linkage mapping by Hoffman et al. (2000) was consistent with that presented in abstract form by Jung et al. (1996) in 2 FCU families. Jung et al. (1996) had also suggested that familial cold urticaria and Muckle-Wells syndrome are probably allelic.
In 3 unrelated families with familial cold autoinflammatory syndrome, Hoffman et al. (2001) found 3 missense mutations in exon 3 of the CIAS1 gene (606416.0001-606416.0003). The families had been described by Shepard (1971), Vlagopoulos et al. (1975), and Wanderer (1979), respectively. In 1 family with Muckle-Wells syndrome, Hoffman et al. (2001) found a mutation in the CIAS1 gene (606416.0004), demonstrating that these 2 syndromes are indeed allelic.
Because of genetic evidence and phenotypic similarity to hereditary periodic fevers (e.g., familial Mediterranean fever, 249100), Hoffman et al. (2001) suggested ‘familial cold autoinflammatory syndrome’ as a more accurate and preferable name for the disorder previously referred to as ‘familial cold urticaria.’
Doeglas et al. (1974); Doeglas and Bleumink (1974); Kaplan et al. (1981); Mathews (1981); McKusick and Goodman (1962); Soter et al. (1976); Tindall et al. (1969); Wasserman et al. (1977)
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Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A., Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nature Genet. 29: 301-305, 2001. [PubMed: 11687797, images, related citations] [Full Text]
Hoffman, H. M., Wright, F. A., Broide, D. H., Wanderer, A. A., Kolodner, R. D. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am. J. Hum. Genet. 66: 1693-1698, 2000. [PubMed: 10741953, related citations] [Full Text]
Jung, M., Ross, B., Wienker, T. F., Preuss, G., Kuester, W., Reis, A. A locus for familial cold urticaria maps to distal chromosome 1q: familial cold urticaria and Muckle-Wells-syndrome are probably allelic. (Abstract) Am. J. Hum. Genet. (Suppl. 59): A223 only, 1996.
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