Autoinflammatory Syndrome, Familial, Behcet-Like M35.2

Behcet-like familial autoinflammatory syndrome is a rare autosomal dominant monogenic autoinflammatory syndrome caused by a heterozygous mutation in the TNFAIP3 gene (191163) on chromosome 6q23.

The disease results from a deficiency of the TNFAIP3 mutant, which physiologically suppresses activation of inflammatory cytokines in the NFKB pathway.

The main clinical manifestations are painful and recurrent mucosal ulcerations of the oral mucosa, gastrointestinal tract, and genital area. Symptoms usually occur in the first decade, but later onset has been reported.

Other variable features include recurrent exanthema, uveitis, and polyarthritis. In many patients, evidence of autoimmune disease is found. Less commonly, patients also have concurrent features of immunodeficiency, including recurrent infections with low numbers of certain white blood cells or impaired immune cell function.

Treatment with tumor necrosis factor (TNFA; 191160) inhibitors is helpful.

Although some of the clinical features of Behcet's-like familial autoinflammatory syndrome are similar to those of Behcet's disease (109650), the more common form of Behcet's disease is thought to be polygenic, typically begins later in early adulthood, and symptoms are usually limited to the mucous membranes (Zhou et al. 2016; Aeschlimann et al. 2018, Kadowaki et al. 2018).

Zhou et al (2016) reported 14 patients, 12 women and 2 men, from 6 unrelated families with autosomal dominant autoinflammatory disorder. Age at disease onset: 2 to 29 years. Patients had oral and genital ulcerations reminiscent of Behcet's disease (see 109650). Some patients also had polyarthritis, rash, uveitis (3x), and inflammation or ulceration of the gastrointestinal tract (4x). Two patients had periodic fever, 1 patient had hemolytic anemia, and 1 patient had idiopathic thrombocytopenia. Lab: Three patients from one family had lupus anticoagulant as well as 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 Behcet-like familial autoinflammatory syndrome , 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. He suffered from diarrhea and intestinal perforations, vasculitis of the small vessels of the central nervous system, hyperglycemia, cataract, and hypertension. All patients developed recurrent painful oral, genital, and/or gastrointestinal ulcers. Other common features occurring at various time points during the disease were gastrointestinal discomfort (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 were immunodeficient with low IgG, poor vaccination response, lymphopenia, and recurrent infections.

Kadowaki et al (2018) reported 30 patients from 9 unrelated Japanese families. TNFAIP3 mutations were detected in 22 patients. In the patients, who ranged in age from 11 months to 71 years, disease symptoms usually appeared in the first decade of life. Clinically, recurrent inflammatory episodes with fever and mucosal ulceration (Behcet-like) were prominent. Furthermore, recurrent aphthous stomatitis, genital ulcers, intestinal inflammations and ulcers. Isolated cases of polyarthritides. In a few patients, polyarthritis occurred before the onset of mucosal ulcers.

More variable features included exanthema, arthralgias, and pathergy phenomena. The frequency of autoimmune diseases was high in this collective: systemic lupus erythematosus (SLE), psoriatic arthritis, juvenile idiopathic arthritis, autoimmune hepatitis, nephritic syndrome, and Hashimoto's thyroiditis. Autoantibodies were detected in several patients. Laboratory tests revealed excessive production of proinflammatory cytokines, including TNFA (191160), TNFR1 (191190), IL6 (147620), IL18 (600953), and IP10 (CXCL10; 147310), suggesting activation of the inflammasome. Treatment with anti-TNF agents successfully induced remission in some patients.

Dong et al (2019) reported a 13-year-old Chinese boy presented with intermittent fever, recurrent exanthema, recurrent tonsillitis, diffuse lymphadenopathy, arthritis, and recurrent gastrointestinal ulcers. Also, elevated ESR; signs of persistent EBV infection. Lab: increased levels of cytotoxic T cells, decreased numbers of helper T cells and CD8+ cytotoxic T cells. IgG was normal, IgE and IgA were elevated. Treatment with acyclovir and steroids resulted in transient clinical improvement.

Gans et al (2020) reported on a 27-year-old man of Ashkenazi Jewish descent who was referred for recurrent fever, infections, oral and genital ulcers, and chronic diarrhea since late childhood. He had a history of recurrent sinopulmonary infections, conjunctivitis, viral bronchitis, skin infections, dental caries, H. pylori gastritis, and EBV viremia. He also had anemia, hepatosplenomegaly. Laboratory tests revealed hypogammaglobulinemia, poor response to vaccines, low numbers of B and CD4+ T cells, decreased numbers of regulatory T cells, poor proliferative T cell response, and decreased numbers of NK cells that were nonfunctional. These findings were consistent with combined immunodeficiency in addition to a complex immune phenotype with autoimmunity and autoinflammation. His cytokine profile showed elevated inflammatory markers, and patient cells showed activation of the NFKB pathway with increased expression of interferon response genes. He responded well to treatment with anakinra and immunoglobulin replacement.

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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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