摘要
目的 总结和分析中国儿童非典型溶血尿毒综合征(atypical hemolytic uremic syndrome,aHUS)的临床表型和基因型特征.方法 该研究为回顾性研究.收集和分析2016年5月至2022年10月首都儿科研究所附属儿童医院肾脏内科收治的6例aHUS患儿的临床资料及基因检测结果.检索万方、中国知网、PubMed等数据库,复习和分析有完善基因筛查资料的中国儿童aHUS的文献.通过文献检索,按照基因检测结果分为基因变异组和非基因变异组,比较两组临床表型、实验室检查、随访和转归的差异.采用Logistic回归分析法分析基因变异组和非基因变异组患儿复发、终末期肾病、死亡风险的差异.结果 本中心纳入的6例aHUS患儿中,男性1例,女性5例,发病年龄7个月～10岁.4例检测出有致病意义的基因变异,分别为补体因子H(CFH)基因变异1例、C3基因变异1例及CFHR1联合CFHR3基因变异2例.6例患儿均有肉眼血尿、大量蛋白尿、高血压和补体C3下降.4例基因变异和2例非基因变异患儿血肌酐平均值分别为153.9、214.3 μmol/L,估算肾小球滤过率平均值分别为26.4、28.9 ml·min1·(1.73 m2)-1,血红蛋白平均值分别为81、57g/L,血小板平均值分别为46×109/L、71×109/L,乳酸脱氢酶分别为2 408、2 106 U/L,CFH抗体阳性者分别为1例和2例,合并神经系统并发症各1例.共检索出包括本中心报道病例在内的中国aHUS患儿97例,男60例,女37例,中位发病年龄5岁;基因变异阳性检出率为58.8％(57/97);基因变异类型以CFHR基因变异为主(43.9％,25/57),其次为CFH基因变异(33.3％,19/57).基因变异组和非基因变异组患儿在发病年龄、性别分布、肉眼血尿比例、大量蛋白尿比例、高血压比例、补体C3下降比例、CFH抗体阳性比例、治疗方式比例、血小板、乳酸脱氢酶等项目上的差异均无统计学意义(均P＞0.05);与基因变异组比较,非基因变异组患儿血肌酐较高(Z=2.311,P=0.021),血红蛋白较低(Z=-2.636,P=0.008).基因变异组和非基因变异组中位随访时间分别为1年和2年,基因变异组未缓解比例和复发比例均显著高于非基因变异组(x2=12.016,P=0.002;x2=4.689,P=0.030).Logistic回归分析结果显示,基因变异组患儿aHUS的复发风险高于非基因变异组(OR=2.807,95％CI 1.014～7.772).结论 中国儿童aHUS基因变异类型以CFHR基因变异为主,存在基因变异患儿预后较差,且易复发.
Abstract
Objective To summarize and analyze the clinical phenotype and genotype characteristics of atypical hemolytic uremic syndrome(aHUS)in Chinese children.Methods It was a retrospective study.The clinical data and genetic results of 6 children with aHUS admitted to Children's Hospital Affiliated to Capital Institute of Pediatrics from May 2016 to October 2022 were analyzed,and literature on Chinese aHUS children with genetic screening data by searching databases such as Wanfang,CNKI,and PubMed were reviewed and summarized.Through literature search,the children with aHUS were divided into genetic variation group and non-genetic variation group according to the results of genetic testing,and the differences of clinical phenotype,laboratory examination,follow-up and outcomes were compared between the two groups.Logistic regression method was used to analyze the risk difference of disease recurrence,end-stage kidney disease and death between genetic variation group and non-genetic variation group.Results Among the 6 aHUS children in this center,there were 1 male and 5 females,with onset age of 7 months to 10 years old.Four patients had gene variations,including 1 patient of complement factor H(CFH)gene variation,1 patient of C3 gene variation,and 2 patients of CFHR1 combined with CFHR3 gene variation.Six children had gross hematuria,proteinuria,hypertension and decreased complement C3.The mean values of serum creatinine in 4 genetic variation and 2 non-genetic variation children were 153.9 μmol/L and 214.3 μmol/L,respectively;the mean values of estimated glomerular filtration rate were 26.4 ml·min-1·(1.73 m2)1 and 28.9 ml·min1·(1.73 m2)-1,respectively;the mean values of hemoglobin were 81 g/L and 57 g/L;the mean values of platelet were 46×109/L and 71× 109/L;the mean values of lactic dehydrogenase were 2 408 U/L and 2 106 U/L,respectively;there were 1 and 2 cases of positive CFH antibody,and 1 and 1 case of nervous system complication,respectively.Ninety-seven aHUS children were retrieved including the reported 6 cases in this center,with 60 males and 37 females,and median onset age of 5 years old.The positive detection rate of genetic variation was 58.8％(57/97).The main type of genetic variation was CFHR gene variation(43.9％,25/57),followed by CFH gene variation(33.3％,19/57).There was no significant difference in onset age,sex distribution,proportions of gross hematuria,massive proteinuria,hypertension,complement C3 decline,positive CFH antibody and treatment method,platelet,and lactic dehydrogenase between genetic variation group and non-genetic variation group(all P＞0.05).Compared with the genetic variation group,non-genetic variation group had higher serum creatinine(Z=2.311,P=0.021)and lower hemoglobin(Z=-2.636,P=0.008).The median follow-up time in genetic variation group and non-genetic variation group was 1 year and 2 years,respectively.The proportions of non-remission and recurrence in the genetic variation group were significantly higher than those in non-genetic variation group(x2=12.016,P=0.002;x2=4.689,P=0.030).Logistic regression analysis showed that the recurrence risk of aHUS in children with genetic mutations was higher than that in children with non-genetic mutations(OR=2.807,95％CI 1.014-7.772).Conclusions The main type of aHUS gene variation in Chinese children is CFHR gene variation,and the children with gene variation have poor prognosis and a higher risk of recurrence.
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