Familial atypical cold urticaria: Description of a new hereditary disease

Received 18 July 2009; received in revised form 10 September 2009; accepted 18 September 2009. published online 12 November 2009.

Background

Acquired cold urticaria (ACU) is usually a self-limited, sporadic, cutaneous disease diagnosed based on history and a positive cold stimulation time test (CSTT) result. We describe 3 unrelated families (A, B, and C) with lifelong atypical cold urticaria distinguished from ACU and familial cold autoinflammatory syndrome.

Objective

We sought to describe a new hereditary disease of cold urticaria and study its pathogenesis.

Methods

Questionnaires, interviews, physical examinations, skin testing, and biopsies were performed. Absolute values, means, and prevalence percentages of data are reported.

Results

Thirty-five subjects are described with familial atypical cold urticaria (FACU; family A, 17; family B, 8; and family C, 10) displaying an autosomal dominant pattern of inheritance. All tested subjects had negative CSTT results. Completed questionnaires from affected and unaffected members of families A and B (n = 35) revealed that all affected subjects had lifelong symptoms that began in early childhood with pruritus, erythema, and urticaria after cold exposure. Angioedema (family A, 23%; family B, 42%) and syncope, near syncope, or both (family A, 46%; family B, 86%) were also present. Triggers included cold atmosphere (100%), aquatic activities (family A, 92%; family B, 100%), handling cold objects (family A, 54%; family B, 71%), and ingestion of cold foods or beverages (family A, 69%; family B, 100%). Skin biopsy specimens demonstrated a mast cell infiltrate with the appearance of degranulation after cold challenge.

Conclusions

FACU is a new cold-induced inherited disease that is different than ACU in its natural history, atmospheric cold elicitation, severity of systemic reactions, and CSTT results. FACU differs from familial cold autoinflammatory syndrome in symptom timing and the absence of fever, chills, and joint pain. The cause is suspected to be mast cell related. Treatment of reactions is similar to that for ACU. Further evaluation of pathogenesis and genetics is warranted.

Key words: Cold urticaria, autosomal dominant, pedigree, questionnaire, cold stimulation time test, evaporative cooling, skin biopsy, mast cell, antihistamine, epinephrine

Abbreviations used: ACU, Acquired cold urticaria, CSTT, Cold stimulation time test, FACU, Familial atypical cold urticaria, FCAS, Familial cold autoinflammatory syndrome

a Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, Calif

b University of Wisconsin Health Allergy and Asthma, Madison, Wis

c Allergy and Asthma Consultants of Montana, Bozeman, Mont

d Children's Specialists of San Diego, Rady Children's Hospital, San Diego, Calif

e San Diego Branch, Ludwig Institute of Cancer Research, La Jolla, Calif

Reprint requests: Hal M. Hoffman, MD, 9500 Gilman Dr, Mail code 0635, La Jolla, CA 92093-0635.

Supported by National Institutes of Health training grant T32 A107469 and the University of California, San Diego, Department of Pediatrics Opportunity Research Grant.

Disclosure of potential conflict of interest: C. Healy receives honoraria from GlaxoSmithKline and Schering-Plough. H. M. Hoffman is a consultant for Regeneron Pharmaceuticals and Novartis Pharmaceuticals. The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(09)01436-5

doi:10.1016/j.jaci.2009.09.035

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