Familial cold autoinflammatory syndrome: Phenotype and genotype of an autosomal dominant periodic fever

Background: Familial cold autoinflammatory syndrome (FCAS), commonly known as familial cold urticaria, is a rare autosomal dominant inflammatory disorder with episodic symptoms precipitated by exposure to cold. Objective: The goal of this study was to formulate clinical diagnostic criteria for FCAS in a large cohort in whom the diagnosis of FCAS was supported by genetic linkage to chromosome 1q44. Methods: We assessed 45 affected and 68 unaffected members from 6 American families. DNA analysis was performed to confirm linkage to chromosome 1q44. Clinical characteristics were determined by means of analysis of detailed questionnaires and medical histories. Results: Pedigree and genetic analyses confirmed autosomal dominant transmission and linkage to chromosome 1q44 in all families. The most consistent symptom during attacks were rash (100%), fever (93%), arthralgia (96%), and conjunctivitis (84%). Age of onset was within the first 6 months of life in 95% of affected subjects. The average delay between cold exposure and onset of symptoms was 2.5 hours, and the average duration of an episode was 12 hours. Renal disease with amyloidosis occurs infrequently in FCAS (2%). Conclusion: The most consistent clinical characteristics of FCAS that discriminate it from other periodic fevers are association with cold exposure, conjunctivitis, age of onset, duration of episodes, and an autosomal dominant inheritance pattern. On the basis of the analysis of genotype and phenotype of FCAS, we formulated clinical diagnostic criteria that can be used to distinguish FCAS from other hereditary periodic fever syndromes.