Autoinflammatory Syndrome, Familial, Behcet-Like

A number sign (#) is used with this entry because of evidence that familial Behcet-like autoinflammatory syndrome (AISBL) is caused by heterozygous mutation in the TNFAIP3 gene (191163) on chromosome 6q23.

Description

Familial Behcet-like autoinflammatory syndrome is an autosomal dominant disorder characterized by ulceration of mucosal surfaces, particularly in the oral and genital areas. Additional more variable features include skin rash, uveitis, and polyarthritis. Symptoms become apparent in the first or second decades. The disorder results from inappropriate activation of inflammatory cytokines; treatment with tumor necrosis factor (TNF; 191160) inhibitors may be beneficial (summary by Zhou et al., 2016).

Clinical Features

Zhou et al. (2016) reported 14 patients, 12 females and 2 males, from 6 unrelated families with an autosomal dominant autoinflammatory disorder. The age at onset ranged from 2 to 16 years in all but 1 patient who had onset at age 29. Patients had oral and genital ulcers reminiscent of Behcet disease (see 109650). Additional features found in some patients included polyarthritis, skin rash, uveitis (3 patients), and inflammation or ulceration in the gastrointestinal tract (4 patients). Two patients had periodic fevers, 1 had hemolytic anemia, and 1 had idiopathic thrombocytopenia. Three patients from 1 family had lupus anticoagulant and other autoantibodies, and 3 additional unrelated patients had antinuclear autoantibodies. Some patients responded to treatment with TNF inhibitors or colchicine.

Inheritance

The transmission pattern of Behcet-like autoinflammatory syndrome in the families reported by Zhou et al. (2016) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of 6 unrelated families with AISBL, Zhou et al. (2016) identified 6 different heterozygous truncating mutations in the TNFAIP3 gene (191163.0001-191163.0006). The mutations in the first 2 families were found by whole-exome sequencing and confirmed by Sanger sequencing; 3 subsequent mutations were found in 3 of 150 probands with a similar disorder who were directly screened for TNFAIP3 mutations. The sixth mutation was found in 1 of 768 individuals diagnosed with Behcet disease (109650) who underwent targeted sequencing. In vitro functional cellular expression studies showed that all mutations failed to suppress TNF-induced NFKB (see 164011) activity, although not in a dominant-negative fashion, which suggested haploinsufficiency as a disease mechanism. Patient cells showed reduced recruitment of TNFAIP3 to the TNFR complex (see 191190) compared to control cells. Patient-derived cells showed increased phosphorylation of IKKA (600664) and IKKB (603258) and subsequent degradation of I-kappa-B-alpha (NFKBIA; 164008), with nuclear translocation of the NFKB p65 subunit (RELA; 164014) together with increased expression of NFKB-mediated proinflammatory cytokines, consistent with activation of the NFKB pathway. Cells expressing the mutant proteins showed defective removal of lys63-linked ubiquitin from TRAF6 (602355), NEMO (IKBKG; 300248), and RIP1 (603453) after stimulation with TNF, indicating inefficient deubiquitination. Levels of proinflammatory cytokines were substantially higher in patient serum compared to controls, and showed evidence of increased IL1B (147720) signaling.