Acquired Cold Urticaria vs. Autoinflammatory Diseases, Genetic and Clinical Profile and Differential Diagnosis: Study of a Cohort of Patients in a Tertiary Reference Centre

Abstract

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 autoinflammatory 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 coldinduced 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 disease. Acquired cold urticaria (ACU) is characterized by the development of itchy wheals after cold exposure. Generalized urticarial skin rashes triggered by cold exposure characterize certain monogenic autoinflammatory 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 order to look for susceptibility factors for the disease. Fifty patients with primary ACU were studied. Germline and post-zygotic variants on the NLRP3, NLRP12, NLRC4 and PLCG2 genes were investigated using nextgeneration 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 pathogenic 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-zygotic or germline pathogenic variants in the NLRP3, NLRP12, NLRC4 and PLCG2 genes.

Cold urticaria – What we know and what we do not know

“…In FCAS, the genetic defect can be heterozygous germline or somatic gain‐of‐function mutations in the NLRP3 gene encoding nucleotide oligomerization domain (NOD)‐, LRR‐ and pyrin domain‐containing protein 3 (NLRP3), also known as cryopyrin (Table 6). 128 In contrast to CAPS, ColdU rarely occurs in infancy, is not associated with fever or arthralgia, 125 and is not related to germline or post‐zygotic variants of NLRP3 , NLRP12 , NLRC4 and PLCG2 genes as demonstrated by next generation sequencing 129 . Unlike the typical itchy wheals in ColdU, CAPS patients show a wide spectrum of skin lesions including flat, non‐itchy or minimally itchy wheals and erythematous patches 130 .…”

“…128 In contrast to CAPS, ColdU rarely occurs in infancy, is not associated with fever or arthralgia, 125 and is not related to germline or post-zygotic variants of NLRP3, NLRP12, NLRC4 and PLCG2 genes as demonstrated by next generation sequencing. 129 Unlike the typical itchy wheals in ColdU, CAPS patients show a wide spectrum of skin lesions including flat, non-itchy or minimally itchy wheals and erythematous patches. 130 The timing of cold-induced lesions is different in ColdU and CAPS (Table 6).…”

Four diseases, PLAID, APLAID, FCAS3 and CVID and one gene (PHOSPHOLIPASE C, GAMMA‐2; PLCG2): Striking clinical phenotypic overlap and difference

“…Familial cold autoinflammatory syndrome is an autosomal dominant immune disorder and autoinflammatory disease characterized by the development of cutaneous urticaria, erythema, and pruritus in response to cold exposure. It is also characterized by the dysfunction of the inflammasome 5 . From this point of view, FCAS3 patients usually display fever and inflammation at different organs, including the skin, joints, central nervous system, and gastrointestinal tract 5 .…”

“…It is also characterized by the dysfunction of the inflammasome 5 . From this point of view, FCAS3 patients usually display fever and inflammation at different organs, including the skin, joints, central nervous system, and gastrointestinal tract 5 . Affected individuals may have additional immunological defects, including antibody deficiency, decreased number of B cells, defective B cells, increased susceptibility to infection, and increased risk of autoimmune disorders 2 …”

“…The PLCG2 gene which is located on the 16th chromosome (16q23.3) encodes phospholipase Cγ2 (PLCG2), a transmembrane signaling enzyme that catalyzes the production of second messenger molecules utilizing calcium as a cofactor and propagates downstream signals in several hematopoietic cells 1 . Recently, heterozygous germline mutations in human PLCG2 were linked to some clinical phenotypes with some overlapping features—PLCγ2‐associated antibody deficiency and immune dysregulation syndrome (PLAID) (OMIM 614878) and autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID) (OMIM 614878) 2‐4 and familial cold autoinflammatory syndrome (FCAS3) (OMIM 614468) 5 . All of them are autosomal dominant inherited diseases.…”