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中华妇幼临床医学杂志(电子版)

Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition) ›› 2023, Vol. 19 ›› Issue (03): 315 -322. doi: 10.3877/cma.j.issn.1673-5250.2023.03.011

Original Article

Haploinsufficiency of A20 complicated with systemic lupus erythematosus: a case report and literature review

Zhijuan Li, Ying Bao†(), Huimei Huang, Nan Yang, Min Zhang, Ying Wang, Pei Qian, Yunhe Niu   

  1. Department of Nephrology, Xi′an Children′s Hospital, Xi′an 710003, Shaanxi Province, China
  • Received:2023-02-19 Revised:2023-05-23 Published:2023-06-01
  • Corresponding author: Ying Bao
  • Supported by:
    Shaanxi Provincial Key Research and Development Plan(2022SF-263)
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Objective

To summarize the clinical characteristics of patient with haploinsufficiency of A20 (HA20) complicated with systemic lupus erythematosus (SLE).

Methods

A case of HA20 complicated with SLE (patient 1) was treated in Xi′an Children′s Hospital in June 2019 was selected in the study. The clinical case data of patient 1 were analyzed retrospectively, and the relevant literature of patients with HA20 complicated with SLE in domestic and foreign databases were retrieved in order to summarize the clinical characteristics of the disease. This study was approved by the Ethics Committee of Xi′an Children′s Hospital (Approval No. 20230048). The guardians were informed consent of the diagnosis and treatment of patient 1.

Results

① The patient 1 was a girl, 5 and a half years old, the main manifestations were pustulosis, fever and joint pain, accompanied by oral ulcer, enlarged liver, spleen and lymph nodes, and short stature. She had a history of hepatosplenomegaly and thrombocytopenia. Her laboratory examinations results showed proteinuria, autoimmune hemolytic anemia, decreased of serum complement (C)3, positive antinuclear antibody (1∶1 000), and positive antism antibody. Renal puncture pathological examination showed mild mesangial proliferative lupus nephritis type Ⅱ (LN-Ⅱ). Gene detection showed that the heterozygous variation of TNFAIP3 gene c. 547 (exon4) C>T, which was a pathogenic mutation and came from her father. She was treated with hormone, cyclosporine, cyclophosphamide and mycophenolate mofetil successively. During the treatment, after hormone reduction, rash occurred again, serum C3 decreased and urine protein increased. Up till now, she has no rash and other manifestations, serum C3 decreased slightly and urine protein is negative. She was final diagnosed with HA20, SLE and LN-Ⅱ. ② Literature review results: There were 14 HA20 complicated with SLE patients retrieved (patients 2-15), the analysis of 15 cases including patient 1 showed that: there were 2 males and 13 females, and the age of onset ranges from 2 months to 29 years old, and 12 patients had the damage of kidney, only 2 patients had genital ulcer. The treatments of these 15 cases was as follows, 12 patients were treated with hormone and 10 patients were treated combined with biological agents. After the treatments, the symptoms of most patients could be controlled, and some patients had repeated symptoms.

Conclusions

The incidence rate of HA20 complicated with SLE is low, and its clinical manifestations are not typical. For SLE children with early onset and poor treatment effect, gene detection is conducive to early diagnosis and treatment for patient of the disease.

Key words: Haploinsufficiency, Lupus erythematosus, systemic, Exanthema, Tumor necrosis factor alpha-induced protein 3, Lupus nephritis, Proteinuria, Child
图1 HA20患儿1(女性，5岁6个月龄)肾脏穿刺组织病理检查结果(图1A：Masson染色，高倍光学显微镜下，可见系膜细胞和基质轻度增生，系膜区可见嗜复红蛋白沉积；图1B：免疫荧光染色显示IgG、IgM、IgA、C3、C1Q，均呈绿色)
图2 HA20患儿1(女性，5岁6个月龄)皮疹(图2A：臀部；图2B：胸腹部。皮疹为片状红斑基础上密集分布呈针尖样脓疱，部分形成脓湖，部分表面可见糜烂、渗出)
图3 HA20患儿1(女性，5岁6个月龄)及其父母TNFAIP3基因Sanger法测序图[图3A、3B：分别为患儿及其父亲该基因c.547(exon 4)C>T杂合突变(箭头所示)；图3C：患儿母亲该基因该位点未见变异]
表1 15例HA20合并SLE患者的临床特征
患者编号 文献(第一作者，发表年) 性别 国家 发病年龄 HA20诊断年龄 发育迟缓 皮肤改变
患儿1 本研究 女 中国 2岁a 8岁2个月 有 有
患儿2 He[5]，2020 女 中国 6岁 15岁 有 结节性红斑，痤疮样病变
患儿3 Kim[6]，2020 女 韩国 2个月 1岁8个月 有 片状红斑，咖啡斑
患者4 Zhang[7]，2022 男 中国 29岁 35岁 无 多发性斑疹
患儿5 Zhang[7]，2022 女 中国 10个月 3岁6个月 无 皮肤狼疮表现
患儿6 Zhang[7]，2022 女 中国 3岁 3岁 无 充血性皮疹
患儿7 Zhang[8]，2021 女 中国 9岁7个月 11岁7个月 有 无
患儿8 Zhou[9]，2016 女 意大利 儿童期 未提及 未提及 无
患儿9 Li[10]，2021 女 中国 7岁 未提及 有 无
患儿10 Kadowaki[11]，2020；Kadowaki[12]，2018 男 日本 1岁3个月 4岁 无 无
患儿11 Aeschlimann[13]，2018 女 美国 10岁 25岁 无 疼痛性皮下皮疹，紫癜，脓疱，毛囊炎
患儿12 Aeschlimann[13]，2018 女 美国 8岁 29岁 无 四肢脓疱，毛囊炎样皮疹
患儿13 Niwano[14]，2022 女 日本 儿童期 30余岁 无 牛皮藓样皮炎
患儿14 Shaheen[15]，2021 女 美国 1岁 14岁 无 特应性皮炎，斑丘疹，盘状红斑
患儿15 Li[16]，2019 女 中国 7岁 14岁 无 无
患者编号 文献(第一作者，发表年) 发热 口腔溃疡 生殖器溃疡 关节炎 淋巴结肿大 血液系统受累
患儿1 本研究 有 有 无 有 有 贫血，血小板降低
患儿2 He[5]，2020 无 有 无 有 无 贫血，淋巴细胞减少，血小板增多
患儿3 Kim[6]，2020 有 有 无 无 无 无
患者4 Zhang[7]，2022 无 无 无 有 无 血小板减少
患儿5 Zhang[7]，2022 无 无 无 无 有 白细胞减少，自身免疫性溶血性贫血
患儿6 Zhang[7]，2022 无 有 无 有 有 自身免疫性溶血性贫血
患儿7 Zhang[8]，2021 无 有 无 无 无 贫血
患儿8 Zhou[9]，2016 无 有 有 未提及 未提及 未提及
患儿9 Li[10]，2021 无 无 无 无 无 有，具体未提及
患儿10 Kadowaki[11]，2020；Kadowaki[12]，2018 有 无 无 无 无 无
患儿11 Aeschlimann[13]，2018 无 有 有 有 无 无
患儿12 Aeschlimann[13]，2018 无 无 无 有 无 无
患儿13 Niwano[14]，2022 有 无 无 无 有 白细胞及血小板降低，贫血
患儿14 Shaheen[15]，2021 有 无 无 无 有 有，具体未提及
患儿15 Li[16]，2019 有 无 无 无 无 白细胞、血红蛋白及血小板均降低
患者编号 文献(第一作者，发表年) 肝脾大 眼部病变 肾脏受累 消化系统受累 其他 家族史
患儿1 本研究 有 无 LN-Ⅱ 无 无 父亲
患儿2 He[5]，2020 无 视网膜血管炎和黄斑变性 轻度蛋白尿 肝炎 肺出血 父亲
患儿3 Kim[6]，2020 无 无 无 肝功能异常 无 父亲
患者4 Zhang[7]，2022 无 分泌物增多 LN-Ⅳ 无 无 母亲
患儿5 Zhang[7]，2022 有 无 LN-Ⅴ 无 肺动脉高压，间质性肺病 无
患儿6 Zhang[7]，2022 有 无 LN-Ⅳ 无 无 无
患儿7 Zhang[8]，2021 无 无 有，未具体提及 无 无 无
患儿8 Zhou[9]，2016 未提及 葡萄膜炎 未提及 未提及 神经系统病变 母亲及姐姐
患儿9 Li[10]，2021 无 无 有，未具体提及 无 心包积液 有，未具体提及
患儿10 Kadowaki[11]，2020；Kadowaki[12]，2018 无 无 肾病综合征 自身免疫性肝炎，肠炎 无 无
患儿11 Aeschlimann[13]，2018 无 无 无 腹泻，吸收不良综合征 中枢神经系统血管炎 姐姐
患儿12 Aeschlimann[13]，2018 无 无 LN-Ⅴ 无 孕期先兆子痫 妹妹
患儿13 Niwano[14]，2022 无 无 肾脏多发梗死，皮质萎缩 无 心肌梗死 母亲及哥哥
患儿14 Shaheen[15]，2021 无 无 非肾病水平蛋白尿 无 支气管扩张，巨噬细胞活化综合征 无
患儿15 Li[16]，2019 肝大 无 血尿、蛋白尿，肾活检肾小球系膜增生LN-Ⅲ 肝纤维化 心包积液，甲状腺功能低下 弟弟及父亲
表2 13例(患者1~7，10~15)HA20合并SLE患者的治疗及预后
患者编号 文献(第一作者，发表年) 激素 IVIG 免疫抑制剂 生物制剂 预后
患儿1 本研究 是 是 ①②③ 否 C3轻度降低，尿蛋白反复1次
患儿2 He[5]，2020 是 否 ①③④⑤ TNF-α抑制剂 未提及
患儿3 Kim[6]，2020 否 否 否 否 皮疹反复
患者4 Zhang[7]，2022 是 否 ③⑥ 否 指标恢复，尿蛋白反复2次
患儿5 Zhang[7]，2022 是 否 ① 贝利尤单抗 指标正常
患儿6 Zhang[7]，2022 是 否 ⑦ JAK抑制剂 指标正常
患儿7 Zhang[8]，2021 是 否 ⑦ TNF-α抑制剂 指标正常
患儿10 Kadowaki[11]，2020；Kadowaki[12]，2018 是 否 ①③⑥ TNF-α抑制剂 未提及
患儿11 Aeschlimann[13]，2018 是 是 ①③④⑤ TNF-α抑制剂 造血干细胞移植，缓解18个月复发
患儿12 Aeschlimann[13]，2018 是 否 ⑦ TNF-α抑制剂 症状改善
患儿13 Niwano[14]，2022 是 否 ⑦ TNF-α抑制剂 症状改善，皮疹消退，抗dSDNA抗体阴性
患儿14 Shaheen[15]，2021 是 是 ③⑦ 利妥昔单抗 症状控制，但反复感染
患儿15 Li[16]，2019 是 否 ③⑦ TNF-α抑制剂 治疗6个月后指标正常
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