以难治性腹泻为主要表现的A20单倍剂量不足3例临床及基因变异分析

doi:10.12372/jcp.2023.22e1398

摘要/Abstract

摘要：

目的分析A20单倍剂量不足（HA20）患儿的临床特征及基因变异，为临床诊治提供线索。方法回顾性分析3例HA20患儿的临床表现、实验室检查结果及消化内镜改变，对患儿及其父母进行全外显子测序（WES），致病变异采用Sanger测序进行验证。结果 3例患儿均为女性，最小发病年龄为生后13天，所有患儿主要表现为反复发热、难治性腹泻，排黏液便或黏液血便，均无眼部病变。例1消化内镜检查可见十二指肠球霜斑样溃疡、出血性胃炎、空肠及回肠下段多发溃疡、回盲部充血；例2消化内镜检查胃部及小肠未见异常，结肠多部位溃疡；例3未行消化内镜检查。WES检测发现患儿均携带TNFAIP3基因杂合变异，分别为c.811C>T, p.R271X（自发变异）、c.292_295dupAACG, p.G99Efs*3（变异来自母亲）及c.133C>T, p.R45X（变异来自母亲）。根据美国医学遗传学与基因组学学会（ACMG）指南，分别为致病性变异、疑似致病性变异、致病性变异。例1予甲基泼尼松龙治疗效果不佳，改用英夫利昔单抗治疗；例2、3在甲基泼尼松龙诱导缓解后分别予阿达木单抗、沙利度胺维持。随访期间所有患儿临床症状均缓解，生长发育情况好转。结论反复发热、口腔溃疡伴难治性腹泻患儿需警惕HA20，基因检测有助于及早明确诊断。

关键词: 发热, 难治性腹泻, 反复口腔溃疡, 全外显子测序, TNFAIP3基因

Abstract:

Objective To analyze the clinical characteristics and TNFAIP3 gene variation of 3 patients with A20 haploinsufficiency of A20 (HA20), so as to provide clues for clinical diagnosis and treatment. Methods The clinical manifestations, laboratory data and digestive endoscopy changes of 3 patients were collected. Whole exome sequencing (WES) was performed on the patients and their parents, and the pathogenic variants were verified by Sanger sequencing. Results All 3 patients were female, and the minimum age of onset was 13 days after birth. No ocular lesions were found in any of the patients who presented with fever, diarrhea, and mucosa-stained feces. Digestive endoscopy in patient 1 showed frost-like ulcers of the duodenum bulb, hemorrhagic gastritis, multiple ulcers in the jejunum and lower ileum, and colonoscopy revealed red hyperaemia in the ileocecum. Digestive endoscopy of patient 2 showed no abnormalities in the stomach and small intestine, and multiple ulcers were found in multiple ulcers in colon. Patient 3 did not undergo digestive endoscopy. WES showed that all patients carried heterozygous variants of TNFAIP3 gene: c.811C>T, p.R271X (spontaneous variant), c.292_295dup, p.G99EfsX3 (a variant inherited from mother) and c.133C>T, p.R45X (a variant inherited from mother). According to ACMG (American College of Medical Genetics and Genomics) guidelines, they are classified as pathogenic variation, suspected pathogenic variation, and pathogenic variation, respectively. Patient 1 was treated with methylprednisolone which was ineffective, and was then treated with infliximab; patient 2 was given adalimumab after methylprednisolone-induced remission, and patient 3 was switched to thalidomide after methylprednisolone-induced remission. The clinical symptoms of 3 patients were relieved, and their growth and development were improved. Conclusion Children with recurrent fever, oral ulcers and refractory diarrhea should be alert to HA20, and genetic testing of suspected patients is helpful for early diagnosis.

Key words: fever, refractory diarrhea, recurrent oral ulcer, whole exome sequencing, TNFAIP3 gene

付海燕, 马莉, 石伟娜, 白革兰, 孙敏, 刘亚丽, 程丽娟, 贾霄云, 李桂桂, 赵世光, 李晓雷, 夏耀芳, 赵瑞芹. 以难治性腹泻为主要表现的A20单倍剂量不足3例临床及基因变异分析[J]. 临床儿科杂志, 2023, 41(11): 839-845.

FU Haiyan, MA Li, SHI Weina, BAI Gelan, SUN Min, LIU Yali, CHENG Lijuan, JIA Xiaoyun, LI Guigui, ZHAO Shiguang, LI Xiaolei, XIA Yaofang, ZHAO Ruiqin. Clinical and genetic variation analysis of A20 haploinsufficiency presented as refractory diarrhea in three children[J]. Journal of Clinical Pediatrics, 2023, 41(11): 839-845.

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