An adult case of suspected A20 haploinsufficiency mimicking polyarteritis nodosa
An adult case of suspected A20 haploinsufficiency mimicking polyarteritis nodosa
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一例疑似 A20 单倍体不足的成人病例，类似结节性多动脉炎
DOI：
10.1093/rheumatology/keac308
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发表时间：
2022
期刊：
影响因子：
5.5
通讯作者：
Yasuda Shinsuke
中科院分区：
文献类型：
--
作者：
Niwano Tomoko;Hosoya Tadashi;Kadowaki Saori;Toyofuku Etsushi;Naruto Takuya;Shimizu Masaki;Ohnishi Hidenori;Koike Ryuji;Morio Tomohiro;Imai Kohsuke;Yoshida Masayuki;Yasuda Shinsuke
亲爱的编辑：我们报告一位年轻的日本女性疑似A20单倍不全（HA20），她在复发性心肌梗死后被诊断出来。根据反复发热和淋巴结病诊断为坏死性淋巴结炎（图1A），她间歇性地接受强的松龙（PSL）治疗。在她20岁出头和30岁出头时，她经历了两次心肌梗死，右冠状动脉完全闭塞，需要支架置入术，没有动脉硬化或血栓栓塞的危险因素（图1B）。她的身体检查结果正常，除了弥漫性脱发，头皮上没有皮疹。大多数实验室检测结果在正常范围内（补充表S1，可在风湿病学在线获取），尽管她的CRP水平在发烧期间暂时升高到30mg /l。除低滴度抗ssa抗体外，所有疾病特异性自身抗体均为阴性。然而，诊断SS的分类标准不符合。腹部对比CT显示双肾多发梗死和皮质萎缩（图1C）。虽然病史中未见肾功能或肝功能障碍，但腹部血管造影显示多发动脉瘤和周围梗阻（图1D和E），提示亚临床血管炎症导致中型动脉多发闭塞事件，以及年轻发病的高血压。胃镜检查、结肠镜检查、脑MRI和PET-CT检查以发现进一步的器官受累，但未发现其他异常发现。怀疑自身炎症性疾病，我们在Kazusa DNA研究所（Kisarazu, Japan）针对430个免疫引起基因的先天错误进行了测序分析。它揭示了杂合错义变异TNFAIP3 (c. 1129G> A, p. V377M)（图3）。VPS13B （c. 11972A> T, p. K3991I）、PIK3R1 （c. 346C> T, p. P116S）和NFAT5 (c. 1669C> G, p. Q557E)，可能分别导致HA20 （TNFAIP3）、Cohen综合征（VPS13B）、活化PI3Kd综合征2 （PIK3R1）和NFAT5单倍不足（NFAT5）。为了评估免疫表型，我们分析了免疫细胞亚群和细胞因子产生能力，并进行了免疫印迹分析，如先前报道的[1,2]，并在风湿病学在线上的补充材料和方法中进行了描述。我们观察到产生il -17的细胞和调节性T细胞的增加（补充表S2，可在风湿病学在线获得）[1,3]。从患者衍生的PBMCs中，脂多糖诱导的TNF-a的产生高于健康对照衍生的PBMCs，而IL-1b则相反，低于直觉（图1G）。此外，我们通过免疫印迹分析发现，NF-jB p65磷酸化增强，A20磷酸化减弱，从而证明A20功能受损（图1H和1）。基于这些发现，我们诊断患者为HA20。虽然我们无法对她的家庭成员进行基因分析，但她的母亲和哥哥经历了与她相似的症状。我们可以通过遗传模式排除Cohen综合征和激活PI3Kd综合征2。不能排除NFAT5单倍功能不全，但本病例的临床特征与报道病例不同（补充表S3，可在风湿病学在线获取）。由于秋水仙碱尚未发现有效，因此开始阿达木单抗治疗，这导致她发烧发作的频率、持续时间和严重程度减弱。一年后，我们进行了随访血管造影，显示动脉瘤没有恶化或改善(补充图1A和…
DEAR EDITOR, We report a young Japanese female with suspected A20 haploinsufficiency (HA20) who was diagnosed after a recurrent myocardial infarction. She was treated with prednisolone (PSL) intermittently under a diagnosis of necrotizing lymphadenitis based on the recurrent fever and lymphadenopathy (Fig. 1A). In her early 20s and 30s, she experienced two episodes of myocardial infarction with complete occlusion of the right coronary artery, requiring stenting intervention, without risk factors for arteriosclerosis or thromboembolism (Fig. 1B). Her physical findings were normal except for diffuse hair loss without rash on the scalp. Most laboratory tests were within normal ranges (Supplementary Table S1, available at Rheumatology online), although her CRP level was temporarily elevated to 30 mg/l during fever. All examined disease-specific autoantibodies were negative except for low-titre anti-SSA antibody. However, the classification criteria for a diagnosis of SS were not met. Abdominal contrast CT revealed multiple infarctions and cortex atrophy in both kidneys (Fig. 1C). Although renal or liver dysfunction was not reported in her history, abdominal angiography revealed multiple aneurysms and peripheral obstructions (Fig. 1D and E), indicating subclinical vascular inflammation causing multiple occlusive events in the medium-sized arteries, and young-onset hypertension. Gastroscopy, colonoscopy, brain MRI, and PET-CT were conducted to detect further organ involvement, but no additional abnormal findings were identified. Suspecting autoinflammatory disorder, we performed sequencing analysis targeting 430 inborn errors of immunity-causing genes at Kazusa DNA Research Institute (Kisarazu, Japan). It revealed heterozygous missense variants TNFAIP3 (c. 1129G> A, p. V377M)(Fig. 1F), VPS13B (c. 11972A> T, p. K3991I), PIK3R1 (c. 346C> T, p. P116S) and NFAT5 (c. 1669C> G, p. Q557E), possibly causing HA20 (TNFAIP3), Cohen syndrome (VPS13B), activated PI3Kd syndrome 2 (PIK3R1) and NFAT5 haploinsufficiency(NFAT5), respectively. To evaluate the immunological phenotype, we analysed the immune cell subsets and cytokine-producing capacity, and performed immunoblot analysis, as reported previously [1, 2] and described in the Supplementary Materials and Methods, available at Rheumatology online. We observed increases in IL-17–producing cells and regulatory T cells (Supplementary Table S2, available at Rheumatology online)[1, 3]. The lipopolysaccharide-induced production of TNF-a from patient-derived PBMCs was higher than that from healthy control–derived PBMCs, whereas IL-1b was counterintuitively lower (Fig. 1G). Additionally, we demonstrated impaired A20 function as shown by enhanced phosphorylation of NF-jB p65 and attenuated phosphorylation of A20 using immunoblot analysis (Fig. 1H and I). Based on these findings, we diagnosed the patient as HA20. Although we could not conduct genetic analysis of her family members, her mother and elder brother experienced episodes similar to hers. We could exclude Cohen syndrome and activated PI3Kd syndrome 2 by the pattern of inheritance. NFAT5 haploinsufficiency could not be excluded, but the clinical features of our case were different from the reported cases (Supplementary Table S3, available at Rheumatology online). Since colchicine has not been found to be effective, adalimumab treatment was started, which resulted in an attenuation of the frequency, duration and severity of her fever attacks. One year later, we conducted a follow-up angiography that revealed no deterioration or improvement of the aneurysms (Supplementary Fig. 1A and …