Acta Dermato-Venereologica 99-12CompleteContent | Page 9

CLINICAL REPORT 1071 Acquired Cold Urticaria vs. Autoinflammatory Diseases, Genetic and Clinical Profile and Differential Diagnosis: Study of a Cohort of Patients in a Tertiary Reference Centre Gustavo DEZA 1 , Anna MENSA-VILARÓ 2,3 , Alvaro MARCH-RODRIGUEZ 1 , Silvia SÁNCHEZ 1 , Ramon M. PUJOL 1 , Juan I. ARÓSTEGUI 2–4# and Ana M. GIMÉNEZ-ARNAU 1# Department of Dermatology, Hospital del Mar – Institut Mar d’Investigacions Mèdiques, Universitat Autònoma de Barcelona (UAB), 2 Department of Immunology, Hospital Clínic, 3 Institut d’Investigacions Biomèdiques August Pi i Sunyer, and 4 University of Barcelona, Barcelona, Spain # These authors contributed equally to this work. 1 Acquired cold urticaria (ACU) is characterized by the development of itchy wheals after cold exposure. Ge- neralized urticarial skin rashes triggered by cold ex- posure characterize certain monogenic autoinflamma- tory diseases (AIDs). The objective of this study is to investigate the presence of variants in genes causing AIDs that present with cold-induced urticarial skin rashes in patients clinically diagnosed with ACU, in or- der to look for susceptibility factors for the disease. Fifty patients with primary ACU were studied. Germ- line and post-zygotic variants on the NLRP3, NLRP12, NLRC4 and PLCG2 genes were investigated using next- generation sequencing technology. Seven patients (14%) carried 8 heterozygous germline variants in the following genes: NLRP3 (n  = 1), NLRP12 (n  = 3), NLRC4 (n  = 1), PLCG2 (n  = 3). No pathogenic or likely pathoge- nic variants were detected, and deep analyses of the sequences obtained did not identify any post-zygotic variant. In conclusion, ACU is not related to post-zy- gotic or germline pathogenic variants in the NLRP3, NLRP12, NLRC4 and PLCG2 genes. Key words: autoinflammatory diseases; cold urticaria; genetic variant; urticaria; urticarial skin rash. Accepted Aug 12, 2019; E-published Aug 13, 2019 Acta Derm Venereol 2019; 99: 1071–1077. Corr: Ana M. Giménez-Arnau, Department of Dermatology, Hospital del Mar – Institut Mar d’Investigacions Mèdiques, Universitat Autònoma de Barcelona (UAB), Passeig Marítim, 25–29, ES-08003 Barcelona, Spain. E-mail: [email protected], [email protected] C old urticaria is a physical urticaria characterized by the development of itchy wheals and/or angioedema after direct contact between the skin and cold air, liquids and/or objects (1–3). Its diagnosis is usually supported by cold-contact stimulation tests (CSTs), in which an immediate wheal is induced after the application of a cold stimulus to the skin (1). Cold urticaria syndromes are very heterogeneous and can be classified into acqui- red and familial disorders (3). Acquired cold urticaria (ACU) are further divided into 2 subgroups: (i) primary (“idiopathic”) and (ii) secondary ACU, depending on the presence of an underlying disease or factor associa- ted with the induction of the cold urticaria symptoms. A particular subtype of ACU, known as atypical ACU, SIGNIFICANCE Acquired cold urticaria represents a subtype of inducible urticaria characterized by the development of itchy wheals after cold exposure. Generalized cold-induced urticarial rashes are also seen in certain monogenic autoinflamma- tory diseases. In the present study, we demonstrated that acquired cold urticaria is not related to the presence of germline and post-zygotic pathogenic variants on genes causing autoinflammatory diseases that present with cold- induced urticarial skin rashes (i.e. NLRP3, NLRP12, NLRC4 and PLCG2 genes). However, the presence of cold urticaria in addition to systemic manifestations, family history and/ or laboratory abnormalities should alert physicians to the potential diagnosis of a monogenic autoinflammatory di- sease. is characterized by the negative responses after CSTs, and therefore, its diagnosis is established mainly on the basis of a detailed clinical history (3). ACU most fre- quently affects young adults, although up to 15–25% of patients may show an onset of symptoms before the age of 18 years (2, 4), with recent evidence suggesting that paediatric-onset patients might exhibit distinctive clinical features (2). Its symptoms are usually limited to cold- exposed skin areas and typically appear a few minutes after exposure to cold air, liquids and/or solids. Exten- sive cold contact may occasionally result in generalized symptoms, including headache, dyspnoea, hypotension or loss of consciousness (1, 5). It is known that ACU is caused by the release of histamine, leukotrienes, platelet activating factor and other proinflammatory mast-cell mediators (3–6). However, the complete pathophysiology of the disease, particularly the atypical ACU, remains undetermined (2). Autoinflammatory diseases (AIDs) are a group of inherited conditions of innate immunity characterized by seemingly unprovoked and recurrent episodes of sterile inflammation. The main subgroups among AIDs are the inflammasomopathies, which are characterized by a dysfunction of the inflammasome, a cytosolic multiprotein complex regulating the pyroptosis and the release of caspase-1 activation-dependent inflammatory cytokines (7). From a clinical point of view, patients with This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3292 Acta Derm Venereol 2019; 99: 1071–1077