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中国循证儿科杂志

中国循证儿科杂志 ›› 2017, Vol. 12 ›› Issue (1): 54-59.

• 论著 • 上一篇    下一篇

非典型溶血尿毒综合征患儿14例临床表型与基因型分析

王春燕1，沈茜1，孙利2，李国民2，吴冰冰3，徐虹1   

  1. 复旦大学附属儿科医院 1肾脏科，上海市肾脏发育和儿童肾脏病研究中心，2 风湿科，3 转化医学中心 上海，201102
  • 收稿日期:2017-01-13 修回日期:2017-02-13 出版日期:2017-02-25 发布日期:2017-02-25
  • 通讯作者: 徐虹

Analysis of genotype-phenotype correlation in 14 patients with atypical hemolytic uremic syndrome

WANG Chun-yan1, SHEN Qian1, SUN Li2, LI Guo-min2, WU Bing-bing3, XU Hong1   

  1. 1 Department of Nephrology, Shanghai Kidney Development & Pediatric Kidney Disease Research Center, 2 Department of Rheumatology, 3 Medical Translational Center，Children's Hospital of Fudan University，Shanghai 201102, China
  • Received:2017-01-13 Revised:2017-02-13 Online:2017-02-25 Published:2017-02-25
  • Contact: XU Hong

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摘要：

目的：对非典型溶血尿毒综合征（aHUS）临床表型和基因型分析了解与预后的关系。方法：纳入临床表现符合血栓性微血管病（TMA）的患儿，通过ELISA法行ADAMTS13酶活性的检测，对ADAMTS13酶活性＞10%，且排除其他类型HUS，行肾脏267个基因panel（包括aHUS已知的与发病相关的C3、C4、C5、CFH、CFB、CFI、MCP、CFHR1、CFHR3、CFHR5、THBD、PLG、DGKE）二代测序，对测序结果阳性的基因行sanger验证。提取纳入的aHUS患儿的随访资料，比较基因突变与未突变患儿预后，系统检索文献，行aHUS临床表型与基因文献复习。结果：14例aHUS患儿进入本文分析，男6例，女8例，5例累及肾脏以外系统。基因检测阳性和阴性者SCr分别为335.3和247.8，eGFR分别为28.8和21.2，C3降低分别为3例和4例，随访时间1~67个月，末次随访结局：基因检测阳性和阴性死亡分别为2例和0例，复发分别为2例和0例，终末期肾病（ESRD）分别为3例和0例，eGFR分别为48和103.7。检索Pubmed数据库，对包括本文病例在内的成人（148例）和儿童（154例）aHUS病例行临床特征和基因型分析，男性病例儿童多于成人，差异有统计学意义；前驱感染（消化和呼吸道）儿童较成人比例高，差异有统计学意义；除神经系统受累、肺泡内出血及高血压外，儿童较成人更易累及其他系统（肝炎、胰腺炎等多器官受损）；成人Scr异常高值大于儿童，差异有统计学意义。CFH突变率欧洲人群高于亚洲，差异有统计学意义。结论：儿童和成人CFH突变均较未突变的aHUS病例预后差，儿童较成人aHUS病例更易累及肾脏、神经以外的系统。

Abstract:

Objective: To investigate the relationship between the genotype and long-term progress in atypical hemolytic uremic syndrome.Methods: Patients diagnosed with thrombotic microangiopathy were included and examined for ADAMTS13 activity. The patients whose ADAMTS13 activity was above 10% were screened for mutations in 267 kidney disease related genes using next generation sequencing. The mutations were confirmed using the Sanger sequencing. The patients were grouped according to their genetic characteristics and compared for the long-term progress. The literatures of aHUS genotype-phenotype were reviewed. Results: Fourteen patients were included in our study, Other organs were involved in 5 patients. 9 of 14 patients (64.3%) were reported with at least one mutation. Heterozygous mutations were found in 3 cases and one case in CFH and CFI genes respectively. One patien was identified with homozygous mutation on MCP, one patient with homozygous mutation on CFHR1 , one with exon 3-5 deletion of the CFHR1, one with combined mutation of C3 and CFB, one with combined CFH exon 20 duplication and exon 4 deletion of CFHR1. Three novel mutations were identified, C3 (c.21G>A), CFH(IVS8+4A>G) and CFI(c.772+1G>T). Comparing the clinical features of mutation carriers and non-carriers, the mutation carrier's kidneys involved the eGFR （mL·min-1·1.73 m-2）were 28.8 and 21.2, respectively, low C3 was found in 4 patients and 3 patients, respectively. During the follow-up for 1-67 months, clinical outcomes varied in mutation-carrier patients, one died during the acute stage and 3 patients progressed to end stage renal disease. Of 3 ESRD patients, one had received renal transplant, 2 experienced recurrence and one died. There were no patient died or progressed to end stage renal disease in mutation non-carrier patients. In literatures, children patients were reported to has a high proportion in trigger events and other organs involvement, Conclusion: CFH mutations lead to poor long-term progression in aHUS patients and Other organs are more easily involved in children.