[A report of clinical characteristics of 2 Chinese pedigrees with haploinsufficiency of A20 and literature review].

Objective: To summarize the clinical characteristics of patients with haploinsufficiency of A20 (HA20). Methods: The clinical manifestations, laboratory examinations, treatment, outcome and genetic analysis of 4 cases with HA20 hospitalized in Peking Union Medical College Hospital were analysed.Further literature review was done after searching articles in PubMed and Wangfang databases with the key words "HA20" "A20 haploinsufficiency" "TNFAIP3" up to the date of September 2019. Results: The 4 patients were a father and a daughter, as well as a mother and a daughter. Their phenotypes were quite variable, but all of them have been suffering from recurrent oral ulcer since childhood. Elevation of C-reactive protein (13-33 mg/L) and erythrocyte sedimentation rate (21-60 mm/1h) were found in these 4 patients, and there was positive antinuclear antibody in proband 1.The father in pedigree 1 and the 2 patients in pedigrees 2 have been diagnosed with Behçet disease and the proband 1 with undifferentiated connective tissue disease. The 2 patients in pedigree 1 have developed Hashimoto's thyroiditis. After gene sequencing analysis, it was found that all the 4 patients have heterozygous nonsense mutations in TNFAIP3 gene, that is, c.811C>T, p.R271X in pedigree 1 and c.133C>T, p.R45X in pedigree 2.The diagnosis of HA20 was eventually established when sequencing results and their clinical manifestations were both compatible with this disease.A total of 21 articles were retrieved, all in English, with a total of 91 cases from 39 families (including the 4 cases reported in this paper). HA20 was reported more often in female (57, 64.8%). Most patients develop symptoms from childhood, but as many as 53.4% (47 cases) are not correctly diagnosed until adulthood. Oral ulcers, genital ulcers, periodic fever, gastrointestinal symptoms, rashes, and arthritis are the primary manifestations.Hashimoto's thyroiditis is the most common autoimmune diseases that HA20 patients coexist with. Laboratory tests were characterized by significantly elevated inflammatory markers and low to moderate titers of autoantibodies in some patients.Most HA20 patients were reported to have nonsense mutations or shift mutations of TNFAIP3 gene, which leads to truncation of A20 protein, and only a small number of patients have missense mutation. In terms of treatment, anti-TNF treatment and anti-interleukin 1 is believed to be an effective and the most optimal therapy. The treatment effect is variable and requires long term observations. Conclusions: The clinical phenotypes of HA20 are complex. For patients with both autoinflammatory and autoimmune characteristics, family history should be inquired in detail and gene sequencing should be performed if necessary.