Autoinflammatory syndrome, familial, Behcet-like 1 M35.1

Familial Behcet-like autoinflammatory syndrome-1 (AIFBL1) is an autosomal dominant, monogenic autoinflammatory disorder characterized predominantly by painful and recurrent mucosal ulcerations of the oral mucosa, gastrointestinal tract, and genital area.

Other variable features include exanthema, uveitis, and polyarthritis associated with a systemic hyperinflammatory state. Evidence of autoimmune disease is found in many patients.

Some patients may also have concurrent features of immunodeficiency, including recurrent infections with leukopenia, or impaired immune cell function.

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Familial Behcet-like autoinflammatory syndrome-1 (AIFBL1) is caused by a heterozygous mutation in the TNFAIP3 gene (191163) on chromosome 6q23. The disease is due to the mutant TNFAIP3 not suppressing the activation of inflammatory cytokines in the NFKB pathway; in this respect, treatment with tumor necrosis factor (TNFA; 191160) inhibitors may be beneficial.

Symptoms usually occur in the first decade, but later onset has been reported (Zhou Q et al. 2016).

Patients present with oral and genital ulcerations reminiscent of Behcet's disease (109650). Some patients also had polyarthritis, exanthema, uveitis, and inflammation or ulceration of the gastrointestinal tract.

Inconstant are:

• Gastrointestinal symptoms (56%).
• polyarthritis and/or arthralgia (56 %)
• exanthema (50 %)
• Periodic fever (50 %)
• Ocular and cardiovascular complaints may also be observed but less frequently (19 %).

Furthermore, hemolytic anemia and idiopathic thrombocytopenia may occur, as well as severe multisystemic inflammation such as CNS vasculitis.

AIFBL2 (301074) caused by a mutation in the ELF4 gene (300775) on chromosome Xq26.

Zhou et al (2016) reported 14 patients, 12 women and 2 men, from 6 unrelated families with autosomal dominant autoinflammatory disorder. The age at disease onset ranged from 2 to 16 years in all except 1 patient, in whom the disease started at age 29 years. Patients had oral and genital ulcerations reminiscent of Behcet's disease (109650). Some patients also had polyarthritis, exanthema, uveitis (3 patients), and inflammation or ulceration of the gastrointestinal tract (4 patients). Two patients had periodic fever, 1 patient had hemolytic anemia, and 1 patient had idiopathic thrombocytopenia. Three patients from one family had lupus anticoagulants and other autoantibodies, and 3 other unrelated patients had antinuclear autoantibodies. Some patients responded to treatment with TNF inhibitors or colchicine.

Aeschlimann et al (2018) reviewed 15 patients from six unrelated families with AIFBL1 previously reported by Zhou et al (2016) and reported an additional patient (P16) who developed mucosal and gastrointestinal ulcerations at 1 week of age and died at 8 years of age. His clinical features were consistent with both Crohn's disease and Behçet's disease. In the patient cohort, disease progression varied widely both between and within families, and some clinical features did not appear for several years. All patients developed recurrent painful oral, genital, and/or gastrointestinal ulcers. Other common features that occurred at different time points in the disease were gastrointestinal symptoms (56%), polyarthritis and/or arthralgia (56%), skin involvement (50%), and recurrent fever (50%). Ocular and cardiovascular complaints were also observed less frequently (19% of patients each). Some patients had severe multisystemic inflammation, including 2 with CNS vasculitis. Laboratory tests usually revealed elevation of acute-phase reactants during relapses and fluctuating levels of various autoantibodies. Seven patients (44%) had recurrent upper and lower respiratory tract infections, both bacterial and viral, and two siblings (P11 and P12 from family 5) had immunodeficiency with low IgG, poor vaccination response, lymphopenia, and recurrent infections. None of the patients developed lymphoma or malignancy.

Kadowaki et al (2018) reported 30 patients from 9 unrelated Japanese families with AIFBL1. Twenty-two patients were confirmed to be carriers of a TNFAIP3 mutation, and 8 patients were clinically diagnosed with the disease due to a Behcet-like phenotype with autosomal dominant inheritance. In the patients, who ranged in age from 11 months to 71 years, disease symptoms usually appeared in the first decade, but in a few they appeared in their teens. The main features included recurrent episodes of inflammation with fever and mucosal ulceration similar to Behcet's disease, although fewer than half of the patients met the full diagnostic criteria for Behcet's. Most patients had recurrent aphthous stomatitis, genital ulcers, or abdominal symptoms due to intestinal inflammation and ulceration. Occasionally, polyarthritis was also observed; in a few patients, polyarthritis occurred before the appearance of mucosal ulcers. The phenotype and severity of the disease were heterogeneous, even within families. Some had only stomatitis, whereas others had more severe systemic involvement with onset in infancy. More variable features included rash, arthralgias, and pathergy. None had uveitis or ocular symptoms. The frequency of autoimmune diseases was high, including systemic lupus erythematosus (SLE), psoriatic arthritis, juvenile idiopathic arthritis, autoimmune hepatitis, nephritic syndrome, and Hashimoto's thyroiditis. Autoantibodies were detected in several patients. Laboratory studies revealed excessive production of proinflammatory cytokines, including TNFA (191160), TNFR1 (191190), IL6 (147620), IL18 (600953), and IP10 (CXCL10; 147310), suggesting activation of the inflammasome. There was also an excess of differentiated T helper 17 (Th17) cells. Treatment with anti-TNF agents successfully induced remission in some patients.

Dong et al (2019) reported a 13-year-old Chinese boy who presented with intermittent fever, diffuse lymphadenopathy, arthritis, and recurrent gastrointestinal ulcers. He also had a skin rash and an elevated erythrocyte sedimentation rate (ESR). He had recurrent tonsillitis since age 2 and persistent EBV infection. Laboratory tests revealed mild abnormalities in certain T-cell subsets, including increased levels of effector memory cytotoxic T cells and decreased numbers of helper T cells and CD8+ cytotoxic T cells. IgG was normal, but IgE and IgA were elevated.

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2. Dong X et al (2019) Novel heterogeneous mutation of TNFAIP3 in a Chinese patient with Behcet-like phenotype and persistent EBV viremia. J Clin Immun 39: 188-194.
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5. Zhou Q et al (2016) Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nature Genet 48: 67-73.