肿瘤坏死因子受体相关周期性发热综合征一家系分析  

A family of tumor necrosis factor receptor-associated periodic syndrome

作　　者：李莎[1] 欧榕琼[1] 张碧红[1] 张燕楠 王海燕[1] 檀卫平[1] Li Sha;Ou Rongqiong;Zhang Bihong;Zhang Yannan;Wang Haiyan;Tan Weiping(Department of Pediatrics,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China;Department of Kidney Transplantation,Third Affiliated Hospital of Sun Yat-sen University,Guangzhou 510760,China)

机构地区：[1]中山大学孙逸仙纪念医院儿科,广州510120 [2]中山大学附属第三医院肾移植科,广州510760

出　　处：《中华儿科杂志》2019年第6期477-482,共6页Chinese Journal of Pediatrics

摘　　要：目的分析肿瘤坏死因子受体相关周期性发热综合征(TRAPS)的临床特征和基因突变特点。方法回顾性分析1个广东普宁家系4例TRAPS患儿及其家族中3例成年患者的临床资料。采用流式细胞术检测CD4+T细胞、CD8+T细胞、B细胞、单核细胞和NK细胞水平;采用酶联免疫吸附测定法检测肿瘤坏死因子受体(TNFR)表达水平;应用二代基因测序分析TNFRSF1A基因突变情况;通过Swiss-Model预测基因突变对TNFRSF1A蛋白三级结构的影响。结果该家系7例患者均以周期性发热为主要临床特点,有关节痛、肌痛、多浆膜炎、眶周水肿和皮疹,伴有发作期急性炎症反应物及白细胞升高。每代均有发病,男女均可受累。发病年龄为6月龄~30岁。患者血浆中的TNFR1水平为0~12.4 ng/L,家系正常成员为18.0~22.2 ng/L,血浆中TNFR2表达水平正常;患者NK细胞水平为0.070±0.034,低于家系正常成员0.152±0.122,T细胞、B细胞、单核细胞表达水平正常。基因检测提示先证者及家系中6例均存在TNFRSF1A点突变,位于外显子3:c.295T>A, p.C99S,突变体三维结构预测结果显示该位点突变导致氨基酸的侧链发生了变化,可能影响与受体的结合,进而影响功能。结论TRAPS主要临床特征包括周期性发热、关节痛、肌痛、多浆膜炎、眶周水肿和皮疹,血浆TNFR1水平显著下降及NK细胞数量减少。基因测序分析显示TNFRSF1A基因存在致病性变异。Objective To analyze the clinical manifestations and gene variations of tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Methods Clinical data and gene testing of four children and three adult relatives in a family from Puning, Guangdong were retrospectively analyzed. CD4+T cells, CD8+T cells, B cells, monocytes and NK cells were assessed by flow cytometry. Plasma level of TNFR receptors were assessed by enzyme linked immunosorbent assay (ELISA). TNFRSF1A gene variation was identified by second generation sequencing. Swiss-Model was used to analyze the potential impact of TNFRSF1A gene variation on its protein tertiary structure. Results For all the patients,periodic fever was the main clinical feature,combined with arthralgia,myalgia,multiple serositis,periorbital edema and migratory cutaneous rash,accompanied with elevated level of acute-phase reactants and increased white blood cell counts during each episode. This disease was found in both gender and every generation in this family. The median age of onset was 2 years, ranging from 6 months to 30 years. The plasma level of TNFR1 of the patients range from 0 to 12.4 ng/L,which was lower than that of the normal controls range from 18.0~22.2 ng/L,while the level of TNFR2 was normal. Also, the numbers of T cells, B cells and monocytes were within normal range;however,number of NK cells in the patients (0.070±0.034) was lower than that in the normal controls (0.152±0.122). The TNFRSF1A variation,located in exon 3: c.295T>A (p.C99S),was found in the proband as well as the other 6 family members,which could induce change of the side chain of amino acid according to the prediction of the three-dimensional structure,subsequently affecting the binding to the receptor. Conclusions TRAPS is characterized by periodic fever,arthralgia,myalgia,multiple serositis,periorbital edema and migratory cutaneous rash,with a significant decrease in plasma level of TNFR1 and NK cells. The gene sequencing analysis revealed a pathogenic variation in TNFRSF1A gene.

关 键 词：发热 遗传性自身炎症性疾病 基因 

分 类 号：R725.9[医药卫生—儿科]