A20单倍剂量不足二家系并文献复习

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

目的总结A20单倍剂量不足(HA20)的临床特点.方法报道北京协和医院收治的2家系4例HA20患者的临床表现、治疗、转归和基因测序结果.并以"A20单倍剂量不足""HA20""TNFAIP3"为关键词,检索截至2019年9月万方数据库和PubMed数据库的文献进行复习.结果4例患者系一对父女及一对母女,临床表现差异较大,但4例患者自幼均有反复口腔溃疡,均有C反应蛋白(13~33 mg/L)、红细胞沉降率(21~60 mm/1h)升高,先证者1还有抗核抗体阳性.先证者1的父亲和先证者2及其母亲曾被诊断为白塞病,先证者1被诊断为未分化结缔组织病.家系1的父女均合并桥本甲状腺炎.基因测序示4例患者均存在TNFAIP3基因杂合的无义突变:家系1为c.811C>T,p.R271X杂合突变,家系2为c.133C>T,p.R45X杂合突变.结合临床表现修正诊断为HA20.检索到的HA20病例报道共21篇,均为英文报道,共计39个家系、91例患者(包括本组4例).患者以女性居多(57例,64.8%),多于儿童时期起病,但多达53.4%(47例)的患者至成年期才被确诊.口腔和(或)生殖器溃疡、周期热、消化道症状、皮疹和关节炎是最常见的临床表现,可合并多种自身免疫性疾病,其中以桥本甲状腺炎最为常见.实验室检查特点为炎症指标明显升高,部分患者存在低至中等滴度的自身抗体.大部分HA20患者存在TNFAIP3基因无义突变或移码突变,导致A20蛋白截短,少部分患者存在错义突变,而干扰其对核因子κB通路的抑制.治疗上,HA20患者可选用白细胞介素1拮抗剂或肿瘤坏死因子拮抗剂治疗,远期预后个体差异大,严重者有死亡风险.结论HA20临床表现复杂,对兼有自身炎症和自身免疫特点的患者,应详细询问家族史,必要时完善基因测序,以帮助患者确诊及产前诊断.

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 Beh?et 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.