SLC12A3 基因新突变致Gitelman 综合征一家系报告

目的探讨Gitelman综合征的基因诊断。方法回顾性分析1例Gitelman综合征患儿的临床资料,及患儿与其父母、姐姐的基因分析结果。结果患儿,男,6岁。因发热、低血钾入院。经检测发现SLC12A3基因位点EXON 21c.2522AG p.(Asp841Gly)杂合宽度和EXON16 c.1946CT p.(Thr649Met)杂合突变,确诊为Gitelman综合征。患儿母亲携带EXON21 c.2522AG p.(Asp841Gly)杂合,患儿父亲和姐姐携带EXON16 c.1946CT p.(Thr649Met)杂合突变。结论SLC12A3基因检测有助于Gitelman综合征诊断,新发现SLC12A3基因突变丰富了Gitelman综合征基因突变谱。     

儿童 Gitelman 综合征 3 例临床特点及基因分析

目的探讨儿童Gitelman综合征的临床及基因突变特点。方法回顾分析3例Gitelman综合征患儿的临床资料。结果 3例患儿均为男性,年龄分别为3、8、10岁。临床表现为低钾血症、低镁血症、碱中毒、高肾素血症、高醛固酮血症。基因检测显示存在SLC12A3基因的复合杂合突变,共发现SLC12A3基因的5个突变位点:c.179CT(Thr60Met)、c.248 GA(Arg 83 Gln)、c.2129 CA(Ser 710 X)、c.2660+1 GA、c.1456 GA(Asp 486 Asn)。患儿确诊后,经补钾、补镁、螺内酯治疗后病情好转。结论儿童出现低钾血症需注意Gitelman综合征,基因检测有助于明确诊断。     

儿童Gitelman综合征SLC12A3基因的复合杂合突变研究

目的探讨儿童Gitelman综合征的临床表现、病理、遗传学异常等。方法对儿童Gitelman综合征临床表现、肾活检明确病理、基因突变位点等进行检查。结果临床表现低血钾、低镁血症、碱中毒,高肾素血症、高醛固酮血症,基因检测发现存在SLC12A3基因的复杂杂合突变,即c.1964GA,p.(Arg655His)联合8号外显子缺失突变、c.2543AT,p.(Asp848Val)联合8号外显子缺失突变。结论儿童Gitclman综合征起病隐匿,复合杂合突变发生率高,基因诊断是确诊手段,儿科医生需要提高认识,以防漏诊误诊。     

儿童低钾性肾小管疾病38例临床分析

目的探讨儿童低钾性肾小管疾病的临床特点以及基因诊断在该类疾病中的应用价值。方法回顾性分析2010年1月至2016年1月上海市儿童医院收治的38例低钾性肾小管疾病患儿的临床资料及基因诊断结果。结果 38例患儿包括肾小管酸中毒Ⅰ型17例,肾小管酸中毒Ⅱ型1例,Bartter综合征11例,Gitelman综合征5例,范可尼综合征4例。临床特点:低钾性肾小管疾病以肌无力、恶心呕吐、多饮多尿、生长发育迟缓为主要的临床症状。在肾脏损害方面,1例范可尼综合征患儿进展至慢性肾脏病(CKD)3期,其余患儿肾功能正常。Bartter综合征、Gitelman综合征和范可尼综合征分别有1例、1例和3例患者出现肾小球性蛋白尿,1例范可尼综合征出现肾小管性蛋白尿。患儿肾小球性和肾小管性尿微量蛋白普遍升高。基因诊断:1例肾小管酸中毒Ⅰ型为ATP6V0A4复合杂合突变,3例Gitelman综合征系SLC12A3复合杂合突变。结论低钾性肾小管疾病的临床表现多样化,以肌无力、恶心呕吐、多饮多尿、生长发育迟缓为主要的临床症状;低钾性肾小管疾病患儿普遍同时存在肾小球和肾小管损伤;基因诊断有助于低钾性肾小管疾病的诊治及遗传咨询。     

SLC25A1基因相关性先天性肌无力综合征二例并文献复习

目的探讨SLC25A1基因相关性先天性肌无力综合征(CMS)的临床及遗传学特征。方法回顾性分析2015年1月至2019年6月复旦大学附属儿科医院诊治的2例SLC25A1基因相关性CMS患儿的临床资料,并以“SLC25A1”“先天性肌无力综合征”为关键词对万方数据知识服务平台、中国期刊全文数据库(CNKI),以“SLC25A1”“congenital myasthenic syndrome”为关键词,对美国国家生物技术中心(NCBI)、生物医学文献数据库(Pubmed)建库至2020年6月收录的论文进行检索。总结SLC25A1基因相关性CMS的临床表型及基因型特点。结果2例患儿均为男性,分别为9岁、2岁,发病年龄均在婴儿期,其共同临床表现除典型的CMS症状(波动性肌无力,包括上睑下垂、斜视、咀嚼无力、声音低弱、四肢无力)外,还具有智力障碍、发育迟缓及代谢异常(尿中2-酮戊二酸升高、乳酸升高或者2-羟基戊二酸尿症),家系全外显子测序检测发现存在SLC25A1基因复合杂合变异。文献检索到3篇英文文献共15例患儿,包括本组2例共17例纳入分析,均于2岁以内起病,9例合并轻度智力低下,1例合并发育迟缓;共发现5个SLC25A1基因变异,包括3个错义变异及1个无义变异、1个缺失变异,其中6个家系中12例患儿携带c.740G>A(R247Q)纯合变异,本组2例患儿均有c.145G>A(V49M)变异。结论SLC25A1基因相关性CMS患儿起病早,多合并智力障碍或者发育迟缓,部分有代谢异常表现,基因型中R247Q和V49M具有重复性。     

儿童Gitelman综合征6例临床分析

目的分析Gitelman综合征的临床表现、实验室检查、诊断和治疗方法,进一步提高诊疗水平。方法回顾性分析2010年9月至2014年6月苏州大学附属儿童医院肾脏科收治的6例Gitelman综合征患儿的临床资料。结果 6例均存在全身乏力等临床表现,以双下肢乏力为主,生化检查示不同程度的低血钾、低血镁及代谢性碱中毒,肾素-醛固酮-血管紧张素Ⅱ水平见不同程度的升高,SLC12A3基因测序阳性,经对症治疗后长期随访,未出现相关并发症。结论儿童Gitelman综合征以双下肢乏力为主要临床表现,伴有低血钾、低血镁等,通过检查尿钙与肌酐比值、血镁、尿镁、肾素活性、血管紧张素Ⅱ和醛固酮水平,结合检测到血清SLC12A3基因上的变异等可确诊。该病治疗以补钾、补镁、醛固酮拮抗剂等多种药物联合应用为主,虽不能治愈,但预后良好。     

肾病综合征合并Duchenne型肌营养不良症1例病例报告

【摘要】 目的 研究肾病综合征合并Duchenne型肌营养不良症患儿的临床特点,探讨肾病综合征与Duchenne型肌营养不良症的可能关系。方法 对2014年5月就诊于湖南省儿童医院肾内科的一例肾病综合征合并Duchenne型肌营养不良症患儿的临床特点、肾脏病理、基因诊断及对激素治疗的反应进行总结。结果 ①临床特点：6岁男孩,有1兄20岁,身体健康,家庭中两系3 代无类似疾病者。该患儿肾病综合征频繁复发,伴有谷草转氨酶、丙转氨酶、肌酸激酶、乳酸脱氢酶等肝酶及肌酶显著升高;肾脏病理为轻度系膜增生性肾小球肾炎。②遗传学检查：染色体核型分析无异常;dystrophy基因52号外显子缺失。结论 肾病综合征合并Duchenne型肌营养不良症患儿表现为难治性肾病,dystrophy基因52号外显子缺失与NS发病无直接联系,但有可能与NS频繁复发有关联,需要进一步研究。     

糖皮质激素受体基因多态性与肾病综合征患儿激素耐药相关性探讨

目的　筛选人类糖皮质激素受体基因 (NR3C1)的多态性 ,并分析其在激素耐药型、激素敏感型肾病综合征患儿以及参照人群 (随机抽取的脐血标本 )中的分布 ,以研究NR3C1多态性与肾病综合征患儿激素耐药的关系。方法　提取 3 9例激素耐药型、67例激素敏感型肾病综合征患儿以及64例参照人群血基因组DNA ,PCR扩增NR3C1中编码人类糖皮质激素受体全部功能区的第 2～ 9α外显子 ,以变性高效液相色谱 (DHPLC)分析检测PCR产物 ,对洗脱曲线异常者进行DNA测序。结果　在总计 170份基因组DNA样本中 ,DHPLC分析发现 12种多态性 ,均经DNA测序证实。另外 ,有 3组多态性呈紧密连锁的单倍型 ( [198G >A + 2 0 0G >A] ,[13 74A >G +IVSG 68_IVSG 63delAAAAAA +IVSH 9C >G + 2 3 82C >T] ,[1896C >T + 2 166C >T + 2 43 0T >C] )。后 2种单倍型为首次报道 ,它们在激素耐药型肾病综合征组的基因型频率 ( 10 .3 %和 15.4% )明显高于敏感型肾病综合征 ( 1.5%和 7.5% ) ,2种单倍型的OR值分别为 7.54和 2 .2 6。其余多态性在各组中出现频率相对较低。结论　在NR3C1基因中筛选出 12处多态性 ;而且新发现的 2种多位点紧密连锁的单倍型可能与肾病综合征患儿发生糖皮质激素耐药有关     

散发性激素耐药型肾病综合征患儿30例足细胞基因突变分析

目的分析散发性激素耐药型肾病综合征(SRNS)儿童足细胞基因突变及其特点。方法研究对象为30例散发性SRNS患儿和50例尿检正常的健康志愿者。采用PCR扩增NPHS1、NPHS2和CD2AP基因全部外显子及其周围的部分内含子,WT1基因外显子8和9及其周围的部分内含子;应用DNA序列直接测定法对其PCR产物进行测序。结果在10例应用激素和免疫抑制剂治疗肾病无缓解的SRNS患儿中,发现1例携带WT1基因杂合突变——1180C>T(R394W),1例携带NPHS1基因复合杂合突变——2677A>G(T893A)和*142T>C,1例携带CD2AP基因杂合突变IVS13-137G>A。在20例应用激素或免疫抑制剂治疗肾病缓解的SRNS患儿中,发现4例患儿携带NPHS1基因单杂合突变——928G>A、IVS8+30C>T、IVS21+14G>A和IVS25-23C>T,1例患儿携带CD2AP基因单杂合突变(IVS7-135G>A)。结论对激素和免疫抑制剂均耐药的SRNS患儿需进行足细胞基因突变分析。     

儿童IgA 肾病合并Alport 综合征2 例报告并文献复习

目的探讨IgA肾病的诊断和鉴别诊断的思路。方法回顾分析2例IgA肾病患儿的临床资料,并复习相关文献。结果2例患儿均为男性,年龄分别为6岁、7岁,临床表现为大量蛋白尿(以白蛋白为主)、低白蛋白血症、高胆固醇血症及持续镜下血尿,均符合肾病综合征诊断,但激素及免疫抑制剂治疗效果欠佳。肾脏病理免疫荧光结合光镜检查符合轻、中度系膜增生性IgA肾病(M1E0S0T0);电镜提示肾小球基底膜病变(分层、断裂、薄厚不均),Alport综合征不除外。进一步基因检测证实存在COL4A5致病基因突变。结论 IgA肾病和Alport综合征二者合并发生较为罕见,对于治疗效果欠佳特别是有相关家族史的IgA肾病患儿,应注意二者同时发生的可能。     

Evaluation and management of steroid-sensitive nephrotic syndrome

PURPOSE OF REVIEW: This review examines new literature published in 2006 and 2007 on steroid-sensitive nephrotic syndrome. RECENT FINDINGS: Steroid-sensitive nephrotic syndrome has long been thought to be due to lymphocyte-derived circulating factors leading to podocyte injury with subsequent proteinuria. New studies support this mechanism and implicate the T helper 2 cytokine IL-13. In addition a genetic mutation in familial nephrotic syndrome has been reported in a child, who responded to corticosteroid therapy. There are new clinical trial data supporting the efficacy of levamisole in steroid-sensitive nephrotic syndrome and preliminary trial data on mycophenolate mofetil supporting its efficacy as a steroid-sparing agent. Case reports support the use of the B cell-depleting antibody rituximab in steroid-sensitive nephrotic syndrome. Finally there is a meta-analysis of six studies suggesting an increase in the incidence of focal and segmental glomerulosclerosis in steroid-sensitive nephrotic syndrome over the last 20 years. SUMMARY: Progress has been made towards elucidating the cause of steroid-sensitive nephrotic syndrome. Data from adequately powered randomized controlled trials are still required to evaluate therapies for frequently relapsing and steroid-dependent steroid-sensitive nephrotic syndrome.     

Rituximab treatment for recurrence of nephrotic syndrome in a pediatric patient after renal transplantation for congenital nephrotic syndrome of Finnish type

Congenital nephrotic syndrome (CNS) of the Finnish type due to mutation in the NPHS-1 gene results in massive proteinuria due to structural abnormality in the glomerular slit diaphragm, and is usually refractory to immunosuppressive therapy. Patients eventually require bilateral nephrectomy and renal replacement therapy, with transplantation being the ultimate goal. Post-transplant recurrence of nephrotic syndrome occurs in about 25% of children and is thought to be immune-mediated secondary to antibodies formed against the nephrin protein in renal allograft. Conventional therapy with calcineurin inhibitors (CNI), cyclophosphamide and corticosteroids with or without plasmapheresis often fails to achieve remission resulting in graft loss in 12-16%. There is limited experience with use of rituximab (RTX) in pediatric organ transplant recipients. We report the first case of post-transplant recurrence of nephrotic syndrome in a 4-yr-old child with CNS due to NPHS-1 mutation in whom CNI, corticosteroid and cyclophosphamide therapy was unsuccessful, but who achieved remission after depletion of B cells with RTX, associated with a decrease in the level of anti-nephrin antibodies. The child remains in remission 5 yr following treatment. Our experience suggests that activated B cells may play a pivotal role in the recurrence of nephrosis after renal transplantation in children with CNS.     

多发性骨溶解综合征伴肾病综合征1例

报道以“浮肿、蛋白尿、关节肿痛及活动受限”为特征的2岁8月龄患儿1例，经基因检测结果为MAFB基因c. 209C>T(p.P70L)杂合变异，该基因为国外已报道的罕见的致病突变，患儿父母无该基因突变。根据患儿临床表现及基因检测结果诊断为多发性骨溶解综合征，同时，对本病进行文献复习，为今后诊断及治疗该类疾病提供借鉴。     

NPHS2 基因突变致遗传性肾病综合征患儿临床特点

目的探讨NPHS2基因突变所致激素耐药型肾病综合征的临床特点。方法回顾分析2例NPHS2基因突变所致激素耐药型肾病综合征患儿的临床资料,并结合文献进行复习。结果 2例患儿均为男性,发病年龄2岁、3岁。临床表现为大量蛋白尿、低白蛋白血症、高胆固醇血症。肾脏病理1例为局灶节段性肾小球硬化,另1例为微小病变。均伴有反复发作性腹股沟斜疝,1例伴左侧睾丸发育不全。相关基因检测均证实存在NPHS2突变。病初即激素耐药,其后激素联合多种免疫抑制剂治疗仍无效。发病3年内均进入终末期肾病阶段。结论对于激素耐药性肾病综合征男性患儿,伴多发疝或睾丸发育异常等肾外表现时,应注意除外NPHS2基因突变所致遗传性肾病综合征可能。     

Simultaneous mutations in the CLCNKB and SLC12A3 genes in two siblings with phenotypic heterogeneity in classic Bartter syndrome

Two siblings (brother and sister) with renal tubular hypokalemic alkalosis underwent clinical, biochemical and molecular investigations. Although the biochemical findings were similar (including hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism and normal blood pressure), the clinical findings were different: the boy, who also presented syndromic signs, developed glomerular proteinuria and renal biopsy revealed focal segmental glomerular sclerosis; the girl showed the typical signs of classic Bartter syndrome. As described in a previous paper, a heterozygous mutation (frameshift 2534delT) was demonstrated in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) of the distal convoluted tubule; the second molecular analysis revealed a compound heterozygous mutation (A61D/V149E) in the CLCNKB chloride channel gene in both subjects, inherited in trans from the parents. The children were finally diagnosed as having classic Bartter syndrome. These cases represent the first report of the simultaneous presence of heterozygous and compound heterozygous mutations in the SLC12A3 and CLCNKB genes, both of which are involved in renal salt losing tubulopathies, and confirm previous observations regarding classic Bartter syndrome phenotype variability in the same kindred.     

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??Objective??To analyze the clinical features and the results of genetic diagnosis in children with hypokalemic renal tubular diseases. Methods??The clinical data of 38 patients with hypokalemic renal tubular diseases were analyzed retrospectively??who were treated in Children’s Hospital Affiliated to Shanghai Jiao Tong University from Jan. 2010 to Jan. 2016. Results??Totally 38 patients with hypokalemic renal tubular diseases were enrolled in this study. There were 18 cases of renal tubular acidosis??RTA?? including 17 cases of type??RTA and 1 case of type?? RTA. There were 11 cases of Bartter syndrome??5 cases of Gitelman syndrome and 4 cases of Fanconi syndrome. The common clinical manifestations of hypokalemic renal tubular diseases included myasthenia??nausea??vomiting??polydipsia??polyurine and growth retardation. One case of Fanconi syndrome progressed to chronic Kidney disease??phase ????while the other
children had normal renal function. Glomerular proteinuria was found in 1??1 and 3 children with Bartter syndrome??Gitelman syndrome and Fanconi syndrome??respectively. Additionally??1 case with Fanconi syndrome has tubular proteinuria. However??urinary trace proteins associated with glomerular and tubular injury commonly elevated in these hypokalemic renal tubular diseases. Genetic analysis showed a new potential heterozygous mutations of ATPV0A4 in type??RTA and three heterozygous mutations of SLC12A3 in Gitelman syndrome. Conclusion??The clinical symptoms vary in patients and are featured mainly by myasthenia??nausea??vomiting??polydipsia??polyurine and growth retardation. Glomerular and tubular injuries are commonly found in hypokalemic renal tubular diseases. Moreover??genetic diagnosis may be helpful in diagnosis??treatment and genetic counseling.     

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目的报告1例肾病综合征、小头畸形、精神运动发育落后GallowayMowat综合征患儿,并进行文献复习。方法患儿(男,13岁)于2004年6月14日入院,根据病史、症状、体征、尿检、血清学及肾组织病理检查结果,结合文献进行分析。结果患儿以血尿、蛋白尿起病,小头畸形伴精神运动发育落后,后出现肾病综合征及肾功能不全,肾活检为局灶节段肾小球硬化。结论肾病综合征伴小头畸形、精神运动发育落后的患儿为GallowayMowat综合征,其肾病综合征出现越早预后越差。     

以激素耐药型肾病综合征起病的Alport综合征15例临床分析

目的 对以儿童激素耐药型肾病综合征(steroid-resistant nephrotic syndrome,SRNS)起病的Alport综合征(Alport syndrome,AS)的临床资料、病理和基因检测情况进行临床分析,以提高对AS的认识.方法 选取2015年1月至2019年12月广州医科大学附属广州市第一人民...     

Focal segmental glomerulosclerosis with and without nephrotic syndrome in children

The clinical presentation, initial laboratory and renal biopsy findings, and course of focal segmental glomerulosclerosis (FSGS) were studied retrospectively in 57 children in order to compare findings in those with and without nephrotic syndrome and to establish factors of prognostic significance. All patients had proteinuria. Eleven patients were otherwise asymptomatic, and nephrotic syndrome did not develop (group 1); 14 patients had asymptomatic proteinuria, but nephrotic syndrome subsequently developed (group 2); 32 patients had nephrotic syndrome (group 3). There were no differences between these three groups with regard to sex, age, initial renal function, incidence of hypertension and hematuria, and pathologic findings. At the latest follow-up, five group 1 patients, six in group 2, and 14 in group 3 had chronic renal failure; the incidence was similar for those with asymptomatic proteinuria and those with nephrotic syndrome. The location of the sclerosis within the glomerulus proved to have prognostic significance. All 12 patients with peripheral FSGS maintained normal renal function, whereas in 25 of the 44 with hilar FSGS chronic renal failure developed.     

Congenital nephrotic syndrome of NPHS1 associated with cardiac malformation

Congenital nephrotic syndrome (CNS) is a rare disease inherited as an autosomally recessive trait and defined as proteinuria manifesting at birth or in the first 3 months of life. The classical form is the Finnish type of CNS (CNF), which is caused by mutations in the nephrin gene (NPHS1). The classical findings include prematurity, large placenta and massive proteinuria. Minor cardiac findings have been reported as a minor functional disorder but CNS with major cardiac malformation is rare. Here we report the case of a Turkish child with CNS with small indel mutation (c.614_621delCACCCCGGinsTT) in exon 6 of NPHS1 and also major cardiac malformation who did not develop end‐stage renal disease until the age of 5 years.