儿童Gitelman综合征临床分析

Clinical analysis of children with Gitelman syndrome

目的探讨儿童Gitelman综合征(GS)的临床表现、实验室检查结果、诊断和治疗方案,进一步提高临床对该病的诊疗水平。方法选择2017年1月至2018年11月,首都儿科研究所附属儿童医院内分泌科收治的9例(No.1~9)GS患儿为研究对象。回顾性分析其临床病例资料,对其临床表现、基因检测、治疗及转归、随访结果进行分析。本研究遵循的程序符合2013年修订的《世界医学协会赫尔辛基宣言》要求。结果①临床表现及诊断结果:6例(No.1、3、4、6、8~9)患儿表现为感染或骨骼畸形,2例(No.2、7)为身材矮小,1例(No.5)为双下肢无力。生化检查结果:所有患儿均存在血K+浓度降低,8例(No.1~8)存在血Mg 2+浓度降低,7例(No.1、3~8)存在代谢性碱中毒,尿液24 h K+浓度均增高,5例(No.2、4、6、8~9)肾小管损害标志物β2微球蛋白增高。基因检测结果:5例(No.1、6~9)患儿均存在SLC12A3基因突变。其中,No.1、8、9患儿为错义突变;No.6患儿为剪切突变与移码突变,并且其移码突变导致mRNA上终止密码子提前出现,氨基酸终止;No.7患儿为移码突变。No.6患儿的移码突变c.578_582dupCCACC及No.9患儿的错义突变c.1084G>A与c.1613G>T,均为在人类基因突变数据库(http://www.hgmd.cf.ac.uk)中尚未报道的新发突变。②治疗结果:对9例患儿采取补充钾剂、螺内酯[1~3 mg/(kg·d)]及门冬氨酸钾镁(1~2片/次,2~3次/d)治疗后,3例(No.5、7~8)患儿出院时血K+浓度尚未完全恢复正常,但是较入院时明显上升,其余6例(No.1~4、6、9)患儿血K+浓度恢复正常。所有患儿出院时,血Mg^2+浓度基本恢复正常。③随访结果:出院后3个月时,9例患儿血K+、Mg^2+浓度均接近正常值;2例(No.2、7)身材矮小患儿的生长速率较治疗前改善;5例(No.2、4、6、8~9)患儿截至随访终点时,肾小管损伤标志物β2微球蛋白升高无进行性加重,其中2例(No.4、8)患儿β2微球蛋白值已基本恢复至正常值。结论儿童GS临床症状不典型,若患儿生化检查结果显示低血K+、Mg^2+浓度,伴尿K+浓度升高,结合动脉血气分析、肾素-血管紧张素Ⅱ和醛固酮值,基因检测发现SLC12A3基因突变,可对GS进行确诊。该病治疗以补钾、补镁、醛固酮拮抗剂等多种药物联合治疗为主,虽然目前尚不能治愈,但是可以使患儿血K+、Mg^2+等维持正常,预后良好。

Objective To explore the clinical manifestations,laboratory tests results,diagnostic and therapeutic methods of Gitelman syndrome(GS)children,to further improve the diagnosis and treatment of this disease.Methods From January 2017 to November 2018,a total of 9 cases(No.1-9)of GS children who were admitted to the Department of Endocrinology,Children′s Hospital,Capital Institute of Pediatrics were selected as study subjects.Their clinical data were collected retrospectively,and the clinical manifestations,genetic tests,treatments and outcomes,follow-up results were analyzed.This study was in line with the requirements of World Medical Association Declaration of Helsinki revised in 2013.Results①Clinical manifestations and diagnostic results:6 cases(No.1,3,4,6,8-9)showed infection or skeletal deformity,2 cases(No.2,7)showed short stature,1 case(No.5)showed weakness of both lower limbs.Results biochemical examinations:all children had decreased blood K+concentration,8 cases(No.1-8)had low blood Mg^2+concentration,7 cases(No.1,3-8)had metabolic alkalosis,all children had increased 24 h urine K+concentration,andβ2 microglobulin the marker of renal tubular damage increased significantly in 5 cases(No.2,4,6,8-9).Results of genetic test:5 children(No.1,6-9)underwent genetic test,and all of them had SLC12A3 gene mutation.No.1,8 and 9 children had missense mutations.No.6 child had a shear mutation and a frameshift mutation,and the frameshift mutation caused the termination codon on mRNA to terminate amino acid in advance.No.7 child had a frameshift mutation.Frameshift mutation c.578_582dupCCACC of No.6 child and missense mutations c.1084G>A and c.1613G>T of No.9 child were new mutations that have not been reported in the Human Gene Mutation Database(http://www.hgmd.cf.ac.uk).②Treatment outcomes:the 9 children with GS received potassium agent supplement,spironolactone[1-3 mg/(kg·d)]and potassium magnesium aspartate(1-2 tablets/times,2-3 times/d).After treatment,blood K+concentrations in 3 children(No.5,7-8)had not fully recovered to normal when discharged,but they were significantly higher than those at admission,and the blood K+concentrations in other 6 children(No.1-4,6,9)increased to normal.The blood Mg^2+concentrations in 9 children all basically returned to normal when discharged.③Follow-up results:concentrations of blood K+and Mg^2+in the 9 children were close to normal levels at 3 months after discharge,and growth rates of No.2 and 7 children with short stature showed improvement compared with that before treatment.Five children(No.2,4,6,8-9)with elevated renal tubular markerβ2 microglobulin had no progressive exacerbation at the end of follow-up,andβ2 microglobulin levels in 2 children(No.4,8)were basically returned to normal.Conclusions The clinical symptoms of GS children are not typical.If the biochemical test results of a child show low concentrations of blood K+and Mg^2+,and increased concentration of urine K+,then arterial blood gas analysis,detections of renin-angiotensinⅡand aldosterone levels,and SLC12A3 gene mutations in genetic test are needed to confirmed the diagnosis of GS children.The treatment of this disease is mainly based on the combination of potassium agents,magnesium agents,and aldosterone antagonists and so on.Although it cannot be cured now,concentrations of blood K+and Mg^2+of GS children can maintain normal,and its prognosis is good.