Familial Cold Autoinflammatory Syndrome 3

A number sign (#) is used with this entry because familial cold autoinflammatory syndrome-3 (FCAS3), also known as PLCG2-associated antibody deficiency and immune dysregulation (PLAID), is caused by heterozygous deletion within the PLCG2 gene (600220) on chromosome 16q23.

See also APLAID (614878), an allelic disorder with some overlapping features.

Description

Familial cold autoinflammatory syndrome-3 is an autosomal dominant immune disorder characterized by the development of cutaneous urticaria, erythema, and pruritus in response to cold exposure. Affected individuals have variable additional immunologic defects, including antibody deficiency, decreased numbers of B cells, defective B cells, increased susceptibility to infection, and increased risk of autoimmune disorders (summary by Ombrello et al., 2012).

For a discussion of genetic heterogeneity of FCAS, see FCAS1 (120100).

Clinical Features

Gandhi et al. (2009) reported 3 unrelated multigenerational families with atypical cold urticaria. Affected individuals developed pruritic erythema with urticaria and sometimes angioedema within 5 minutes after exposure to cold. Most patients had onset in the first 6 months of life, and all had lifelong duration of the symptoms, although most noted a subjective improvement of the severity of the symptoms after age 30 years. Evaporative cooling appeared to be the most significant trigger, as all patients reported symptoms after cold exposure. For example, a patient's tear at room temperature produced erythema along the line of the teardrop; skin submerged in warm water and then exposed to room temperature became pruritic and erythematous; and cutaneous testing showed that evaporation of water drops produced erythema and urticaria at the site of the drop. Outdoor air cold challenge resulted in erythema and isolated urticarial lesions over unprotected skin. Localized cutaneous reactions did not generalize, and most resolved within 30 minutes of rewarming. A questionnaire was administered to 2 families. A history of atopy was reported in 84% of patients in 1 family, and in 14% in a second family. Triggers included cold atmosphere (100%), aquatic activities (92% and 100% of patients in the 2 families, respectively), handling cold objects (54% and 71%, respectively), and ingestion of cold foods or beverages (69% and 100%, respectively). Ingestion of cold foods or beverages caused oropharyngeal swelling in 29% and 43% of patients from each family, respectively. Other complications included syncope or near syncope (46% and 86%, respectively), usually related to emergence from water. All patients had pruritus and erythema, but angioedema occurred in less than 50% of patients. However, all affected individuals had negative cold stimulation time test (CSTT) results, with erythema but no wheal formation after direct skin contact with ice followed by a 5-minute rewarming period at room temperature. Gandhi et al. (2009) suggested that the phenomenon in these families occurred when a cooling threshold is reached that triggers the cutaneous symptoms, and that this threshold is likely warmer than that of the ice-cube test. Skin biopsy specimens showed a mast cell infiltrate with the appearance of degranulation after cold challenge. The disorder could be distinguished from familial cold autoinflammatory syndrome (FCAS1; 120100) by the lack of severe systemic involvement and from acquired cold urticaria by the negative CSTT test.

Ombrello et al. (2012) reported 3 unrelated families with FCAS3, including 1 family reported by Gandhi et al. (2009). All patients had negative results on skin testing with ice-cube and cold-water immersion, but had positive results on skin testing for evaporative cooling and generalized exposure to cold air. In addition, 26 of 27 patients tested showed immunologic defects, including antibody deficiency (75%), recurrent infections (56%), and autoantibodies or autoimmune disease (56%). Seven individuals had cutaneous nodular granulomatous disease: 4 had persistent granulomatous skin disease and 3 had resolution of the symptoms in infancy. Laboratory studies showed decreased serum IgA and IgM, decreased circulating B cells, decreased memory B cells, and decreased natural killer cells. Most had increased IgE.

Inheritance

The transmission pattern of FCAS3 in the families reported by Gandhi et al. (2009) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of 3 unrelated families with FCAS3, Ombrello et al. (2012) identified 3 different heterozygous intragenic deletions in the PLCG2 gene (600220.0001-600220.0003). The mutations were found by linkage analysis followed by candidate gene sequencing. Five of the 6 deletion breakpoints occurred within repetitive elements. Each of the 3 deletions involved the C-terminal Src-homology-2 (cSH2) domain, which is autoinhibitory and normally prevents constitutive enzymatic function. Transfection of COS-7 cells with PLCG2 constructs lacking the full domain, a deletion of exon 19, or a deletion of exons 20-22 resulted in increased basal and Rac-activated phospholipase activity compared to wildtype. Despite this gain of function, distal signaling and PLCG2-dependent functions were decreased in patient immune cells. The paradoxical loss of downstream function may have resulted from chronic signaling. Patient B cells and natural killer cells both showed defective calcium flux in response to receptor activation on their cell surfaces. However, patient B cells showed increased calcium levels and increased activation with decreasing temperature, whereas control cells did not. Transfection of mutant PLCG2 into mast cells led to spontaneous degranulation at 20 degrees Celsius, which was not seen in controls. The findings indicated that defective receptor signaling in mutant B cells was temperature-dependent and caused abnormal activation and class-switching, resulting in antibody deficiency and impaired central tolerance. The increased activation of mast cells at subphysiologic temperatures was responsible for the cold urticaria. Ombrello et al. (2012) proposed the designation 'PLCG2-associated antibody deficiency and immune dysregulation (PLAID)' to refer to this disorder.