Li Guomin, Li Yifan, Liu Haimei, Shi Yu, Guan Wanzhen, Zhang Tao, Yao Wen, Wu Bingbing, Xu Hong, Sun Li
Department of Rheumatology.
Medical Transformation Centre, Children's Hospital of Fudan University, Shanghai, China.
Medicine (Baltimore). 2020 May;99(20):e20232. doi: 10.1097/MD.0000000000020232.
Systemic lupus erythematosus (SLE) is a chronic, rare autoimmune disease. In recent years, multiple monogenic diseases with early onset autoimmunity and lymphoproliferation have been identified, such as autoimmune lymphoproliferative syndrome, rat sarcoma (RAS)-associated autoimmune leukoproliferative disease, signal transducer and activator of transcription 3 gain-of-function syndrome and interleukin-2 receptor α deficiency. Therefore, we performed whole-exome sequencing in children with SLE with lymphoproliferation to identify genes associated with these conditions.We enrolled 7 patients with SLE with lymphoproliferation from different families. Demographic data, clinical manifestations, laboratory and histopathologic findings, treatment, and outcome were documented. Whole-exome sequencing was performed in 7 patients and their families. Suspected variants were confirmed by Sanger sequencing. Protein levels were detected in patients with gene mutations by western blot.Four patients were male, and 3 were female. No consanguinity was reported within the 7 families. The average age at onset was 5.0 years (range: 1.2-10.0 years). The most common features were renal (7/7 patients) and hematologic (6/7 patients) involvement and recurrent fever (6/7 patients), while only 2 patients presented with skin involvement. Antinuclear antibodies at a titer of ≥1:320 were positive in all patients. All patients fulfilled four 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for the classification of SLE. We identified a somatic activating NRAS variant (c.38 A>G, p.G13C) in peripheral venous blood from 4 patients, at levels ranging from 8.8% to 42.8% in variant tissues that were absent from their parents. B cell lymphoma (BCL)-2-interacting mediator of cell death levels in peripheral blood mononuclear cells from 4 patients were markedly reduced, whereas those in the control were normal. Another 2 mutations, c.559C>T (p.Q187X) in the TNFAIP3 gene and c.3061G>A (p.E1021K) in the PIK3CD gene were detected in 2 patients.The SLE is a novel phenotype of somatic mutations in the NRAS gene and germline mutations in the PI3CKD gene. These genes, NRAS, TNFAIP3, and PIK3CD, should be considered candidates for children with SLE with lymphoproliferation. If patients with SLE and lymphoproliferation present with renal and hematologic involvement and recurrent fever, they need gene testing, especially male patients.
系统性红斑狼疮（SLE）是一种慢性、罕见的自身免疫性疾病。近年来，已发现多种伴有早发性自身免疫和淋巴细胞增殖的单基因疾病，如自身免疫性淋巴细胞增殖综合征、大鼠肉瘤（RAS）相关的自身免疫性白细胞增殖性疾病、信号转导和转录激活因子3功能获得综合征以及白细胞介素-2受体α缺乏症。因此，我们对伴有淋巴细胞增殖的SLE患儿进行了全外显子组测序，以确定与这些病症相关的基因。我们纳入了来自不同家庭的7例伴有淋巴细胞增殖的SLE患者。记录了人口统计学数据、临床表现、实验室和组织病理学检查结果、治疗情况及预后。对7例患者及其家属进行了全外显子组测序。通过桑格测序法对疑似变异进行了确认。通过蛋白质免疫印迹法检测了基因突变患者的蛋白质水平。4例患者为男性，3例为女性。这7个家庭中均未报告近亲结婚情况。发病的平均年龄为5.0岁（范围：1.2 - 10.0岁）。最常见的特征是肾脏受累（7/7例患者）、血液系统受累（6/7例患者）和反复发热（6/7例患者），而只有2例患者出现皮肤受累。所有患者的抗核抗体滴度≥1:320均呈阳性。所有患者均符合2019年欧洲抗风湿病联盟/美国风湿病学会（EULAR/ACR）的SLE分类四项标准。我们在4例患者的外周静脉血中发现了一种体细胞激活型NRAS变异（c.38 A>G，p.G13C），在其父母不存在变异的组织中，变异水平在8.8%至42.8%之间。4例患者外周血单个核细胞中的细胞死亡B细胞淋巴瘤（BCL）-2相互作用介质水平明显降低，而对照组则正常。在2例患者中检测到另外2种突变，分别为TNFAIP3基因中的c.559C>T（p.Q187X）和PIK3CD基因中的c.3061G>A（p.E1021K）。SLE是NRAS基因体细胞突变和PI3CKD基因种系突变的一种新表型。NRAS、TNFAIP3和PIK3CD这些基因应被视为伴有淋巴细胞增殖的SLE患儿的候选基因。如果伴有淋巴细胞增殖的SLE患者出现肾脏和血液系统受累以及反复发热，他们需要进行基因检测，尤其是男性患者。
