20例NPHP1基因缺陷肾单位消耗病患者的临床和基因突变特点  

Clinical features and genotypes of 20 patients with nephronophthisis associated with NPHP1 gene defect

作　　者：赖佳泳 孙良忠 刘雅清[2] 林宏容 岳智慧[3] 王海燕[4] 李敏[1] 蔡勇 艾军[5] 魏海霞 Lai Jiayong;Sun Liangzhong;Liu Yaqing;Lin Hongrong;Yue Zhihui;Wang Haiyan;Li Min;Cai Yong;Ai Jun;Wei Haixia(Department of Pediatrics,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;Department of Pediatrics,the First Affiliated Hospital,Gannan Medical University,Ganzhou 341000,China;Department of Pediatrics,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China;Department of Pediatrics,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China;Department of Nephrology,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China)

机构地区：[1]南方医科大学南方医院儿科,广州510515 [2]赣南医学院第一附属医院儿科,赣州341000 [3]中山大学附属第一医院儿科,广州510080 [4]中山大学孙逸仙纪念医院儿科,广州510120 [5]南方医科大学南方医院肾内科,广州510515

出　　处：《中华肾脏病杂志》2024年第4期277-288,共12页Chinese Journal of Nephrology

基　　金：国家自然科学基金面上项目(81670610);广东省自然科学基金(2022A1515012307,2020A1515010286)。

摘　　要：目的探讨1型肾单位消耗病(nephronophthisis,NPH)的临床表型及NPHP1基因突变特点。方法本研究为病例系列分析,回顾性收集初步诊断1型NPH患者及其父母的外周血标本、临床、影像和病理资料。通过二代测序或微卫星标记检测NPHP1基因变异。结果(1)本研究中,16个家系20例患者确诊为1型NPH。起病中位年龄为9.5岁(3.0~21.0岁),发病至确诊的平均时间为2.1年(0.1~6.5年)。首诊表现方面,肾功能不全7例(35.0%),多饮、多尿或夜尿增多8例(40.0%),贫血4例(20.0%),生长迟缓7例(35.0%),其中1例以生长迟缓及胸廓畸形为首诊表现。肾脏表现方面,10例(50.0%)尿常规检查尿蛋白阴性,10例(50.0%)有少量蛋白尿,均无血尿;首诊时18例(90.0%)患者有不同程度的肾功能损害,进展至慢性肾脏病5期的中位年龄为12岁(9.1~16.5岁)。17例接受尿蛋白成分分析患者中,15例存在α1微球蛋白和β2微球蛋白升高,包括6例尿常规检查尿蛋白阴性患者。11例(55.0%)患者双肾体积正常,9例(45.0%)肾脏体积缩小,其中7例双肾体积缩小,2例单个肾脏体积缩小。B超及磁共振水成像检查显示,12例(60.0%)患者皮髓质交接处和/或肾髓质处有单发或多发肾囊肿,8例(40.0%)未见囊肿。9例患者完成了肾活检,均可见肾小管萎缩及管腔扩张、肾小管基底膜增厚或分层、间质纤维化及炎性细胞浸润。5例存在肾外表现,如Senior-Loken综合征、弱视或屈光不正、Cogan综合征、肝囊肿等。16个家系20例确诊患者中,NPHP1外显子(exon 1~20)纯合缺失发生在8个家系10例患者,杂合缺失伴点突变发生在5个家系7例患者,复合杂合点突变发生在3个家系3例患者,不同基因突变类型患者的临床表型(性别、肾脏体积、囊肿形成、尿蛋白)的差异均无统计学意义(均P>0.05)。16例进行了基因二代测序(靶向外显子组测序和全外显子组测序),其中8例合并其他纤毛病致病基因变异;而与无合并其Objective To explore the clinical features and genotypes of patients with nephronophthisis type 1(NPH1)associated with NPHP1 gene defect.Methods It was a case series analysis.Clinical data and blood samples of patients who were suspected of NPH1 were collected retrospectively.Next generation sequencing(NGS)or microsatellite markers(MMS)were used to detect the variations and homozygous deletion of NPHP1.Results(1)In this study,a total of 20 patients from 16 families were diagnosed as NPH1 with NPHP1 variations and/or homozygous deletions.The median onset age of the patients was 9.5 years old(ranging from 3.0 to 21 years old),and the mean time from onset to diagnosis was 2.1 years(ranging from 0.1 to 6.5 years).The clinical manifestations of the first diagnosis were renal insufficiency in 7 cases(35.0%),polydipsia,polyuria or nocturia in 8 cases(40.0%),anemia in 4 cases(20.0%),and growth retardation in 7 cases(35.0%),of which 1 case was first diagnosed with growth retardation and thoracic malformation.In terms of renal manifestations,10 patients(50.0%)exhibited negative urinary protein by urine routine test,while 10 patients(50.0%)presented with a small amount of proteinuria.Notably,none of the patients displayed hematuria.At first diagnosis,18 patients(90.0%)exhibited varying degrees of renal impairment,and the median age of progression to stage 5 chronic kidney disease was 12 years(ranging from 9.1 to 16.5 years).Of the 17 patients who underwent urine protein composition analysis,15 had elevatedα1 microglobulin andβ2 microglobulin,including 6 patients with negative urine routine test.The volume of the kidney was normal in 11 patients(55.0%)and decreased in 9 patients(45.0%),including 7 patients with both kidneys affected and 2 patients with a single kidney affected.B-ultrasonography and magnetic resonance hydrography showed that 12 patients(60.0%)presented with single or multiple renal cysts located at the cortical medullary junction and/or renal medulla,and 8 patients(40.0%)had no cyst.Renal biopsy performed o

关 键 词：突变 囊肿 纤毛病 肾单位消耗病 NPHP1 肾囊肿 

分 类 号：R692[医药卫生—泌尿科学]