Autoinflammatory diseases are a heterogeneous group of disorders caused by dysregulation in the innate immune system. The protein A20, encoded by TNFAIP3, is involved in the negative regulation of nuclear factor-κB signaling. In 2016, heterozygous mutations in the TNFAIP3 gene have been found to cause A20 haploinsufficiency, presented as an early-onset systemic inflammation that resembles Behçet’s disease.
We presented an 8-year-old boy referred to our hospital at the age of 4 with history of recurrent pain in lower limbs. He developed recurrent oral and genital aphthae, conjunctivitis and headache. He also suffered self-limited fever, abdominal pain, diarrhea and arthralgia. The patient responded poorly to colchicine requiring methotrexate. Laboratory analysis revealed high serum level of IgE (800 UI/mL) and normal IgG, IgA and IgM levels. Tests for autoantibodies and HLA-B51 were negative. The family history showed 3 patients with recurrent oral ulcer and similar symptoms, members over 3 generations in the same family (his sister, mother and grandmother).
Mutation analysis of TNFAIP3 revealed the novel monoallelic (p.W356R) variant and in silico studies predicted a deleterious effect on protein function. No mutations were found in MEFV, MVK and TNFRSF1A genes. The variant is segregated in the family members with the autoinflammatory disease. After genetic diagnosis he began treatment with adalimumab with considerable clinical improvement.
Discovery of new monogenetic autoinflamatory diseases such as A20 haploinsufficiency helps to advance our understanding of disease pathogenesis and to develop targeted therapies for them.