■A20单倍功能不全(HA20)是由TNFAIP3基因中功能突变的丧失引起的单基因常染色体显性遗传自身炎性疾病。与HA20相关的主要自身免疫表型差异显着,出现发烧,复发性口腔和生殖器溃疡,皮疹,胃肠道和肌肉骨骼症状,和其他临床表现,所有这些都表明自身炎症性疾病的早期发作。在GWAS研究中报道了TNFAIP3和T1DM之间的遗传连锁。然而,仅报道了少数HA20合并T1DM的病例。
■一名自19年以来有1型糖尿病病史的39岁男子入住内分泌代谢科,中国医科大学附属第一医院.他还患有复发性和轻微的口腔溃疡,因为儿童早期。他的实验室评估结果显示胰岛功能降低,正常的血脂,HbA1c为7%,谷氨酸脱羧酶抗体升高,肝转氨酶升高,甲状腺功能正常的甲状腺相关抗体升高。值得注意的是,该患者在青春期被诊断出从未患有酮症酸中毒,尽管疾病持续时间长,但胰岛仍在运作,他的肝功能异常无法得到合理解释,他有早发性Behcet样疾病症状。因此,尽管他正在接受糖尿病的常规随访,我们与他进行了沟通,并获得了基因检测的同意。全外显子测序揭示了TNFAIP3基因中一个新的c.1467_1468delinsAT杂合突变,该突变位于外显子7,导致停止型突变p.Q490*。血糖控制良好但轻度波动,患者接受了长效和短效胰岛素的强化胰岛素治疗.随访期间使用熊去氧胆酸0.75mg/d可改善肝功能。
■我们报告了TNFAIP3中的一种新的致病突变,该突变导致T1DM患者的HA20。此外,我们分析了此类患者的临床特征,并总结了5例HA20合并T1DM的病例。当T1DM合并自身免疫性疾病或其他临床表现时,如口腔和/或生殖器溃疡和慢性肝损伤,必须考虑HA20的可能性。在此类患者中,早期和明确的HA20诊断可能会抑制迟发性自身免疫性疾病的进展,包括T1DM。
Haploinsufficiency of A20 (HA20) is a monogenic autosomal-dominant genetic autoinflammatory disease caused by loss of function mutations in the TNFAIP3 gene. The predominant autoimmune phenotype associated with HA20 varies significantly, presenting with fever, recurrent oral and genital ulcers, skin rash, gastrointestinal and musculoskeletal symptoms, and other clinical manifestations, all of which indicate an early-onset of autoinflammatory disorder. Genetic linkage between TNFAIP3 and T1DM was reported in GWAS studies. However, only a few cases of HA20 combined with T1DM have been reported.
A 39-year-old man with a history of type 1 diabetes mellitus since 19 years was admitted to the Department of Endocrinology and Metabolism, First Affiliated Hospital of China Medical University. He also suffered from recurring and minor mouth ulcers since early childhood. His laboratory evaluation results revealed reduced islet function, normal lipid profile, HbA1c of 7%, elevated glutamate decarboxylase antibodies, elevated hepatic transaminases, and elevated thyroid-related antibodies with normal thyroid function. Notably, the patient was diagnosed in adolescence and never had ketoacidosis, the islets were functioning despite the long disease duration, his abnormal liver function could not be reasonably explained, and he had early onset Behcet\'s-like disease symptom. Hence, although he was on routine follow-up for diabetes, we communicated with him and obtained consent for genetic testing. Whole-exome sequencing revealed a novel c.1467_1468delinsAT heterozygous mutation in the gene TNFAIP3, which is located in exon 7, resulting in a stop-gained type mutation p.Q490*. With good but mild fluctuating glycemic control, the patient received intensive insulin therapy with long-acting and short-acting insulin. The liver function was improved by using ursodeoxycholic acid 0.75 mg/d during the follow-up.
We report a novel pathogenic mutation in TNFAIP3 that results in HA20 in a patient with T1DM. In addition, we analyzed the clinical feathers of such patients and summarized the cases of five patients with HA20 co-presented with T1DM. When T1DM co-occurs with autoimmune diseases or other clinical manifestations, such as oral and/or genital ulcers and chronic liver damage, the possibility of an HA20 must be considered. Early and definitive diagnosis of HA20 in such patients may inhibit the progression of late-onset autoimmune diseases, including T1DM.