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Title: [Clinical and pathological features and mutational types of WT1 mutation-associated nephropathy].
Author: Sun LZ, Wang HY, Li M, Lin HR, Wu JL, Tang W, Li YJ, Yue ZH, Liu T, Chen HM, Hu MY.
Journal: Zhonghua Er Ke Za Zhi; 2018 Oct 02; 56(10):769-774. PubMed ID: 30293282.
Abstract:
Objective: To explore the clinical and pathological features and mutational types and their relations with WT1 mutation-associated nephropathy (WT1MAN). Methods: The clinical and pathological data and the results of WT1 mutation analysis of the cases from Nanfang Hospital of Southern Medical University, Sun Yat-sen Memorial Hospital and The First Affiliated Hospital of Sun Yat-sen University whom we recruited recently and reported during the last ten years were analyzed. Results: Totally, 20 cases (6 males and 14 females), included 5 newly diagnosed cases, were recruited. (1) Ten children were diagnosed with Denys-Drash syndrome (DDS): The median onset age of proteinuria was 1 year and 7 months. Diffuse mesangial sclerosis (DMS) were revealed in 3 cases, minimal lesions (MCD) in 4 cases, and focal segmental glomerulosclerosis (FSGS) in 1 case; renal pathology was not available in the other 2 cases. Glomerular basement membrane (GBM) thickening was observed in 2 cases. Calcineurin inhibitors (CNIs) were administered in 5 cases, complete remission of proteinuria was observed in 3 cases, partial remission in the other 2 cases. Genetic analysis revealed that six cases had WT1 missense mutation, 3 had nonsense mutation, and 1 had frameshift mutation. (2) Two cases were diagnosed with Frasier syndrome (FS): proteinuria was observed at 1 year and 1 month of age and 1 year and 9 months of age, respectively. FSGS with GBM layering were observed in both cases. They progressed to ESRD at 1 year and 6 months of age and 6 years and 6 months of age, respectively. CNI was tried in 1 case with partial proteinuria remission. Both patients were detected to have WT1 splice mutation. (3) Isolated nephropathy (IN) was observed in 8 cases: three had splice mutation, 5 had missense mutation. Of the 3 patients with splice mutation, one was found to have nephropathy and renal failure at the age of 5 months. The other two cases (1 was FSGS and another MCD), both had GBM layering. CNIs were tried on both of them, one got partial remission with normal renal function at the age of fourteen years, the other one had no response and entered ESRD at the age of 6 years and 9 months. Of the 5 cases with missense mutation, 3 had DMS, 2 of them entered ESRD within 6 months of age, another case had DMS entered ESRD at 9 years of age. One case with FSGS, was treated with CNIs and got complete remission. Conclusions: Slow progression (7/10) nephropathy was observed in DDS patients. Missense mutation (11/20) was the most common type of WT1 variants, followed by splice mutation (5/20) in this group of patients. Early onset nephropathy (4/5), rapid progression (4/5) and GBM layering (4/4) wereobserved in patients with splice mutation. CNI was effective in reducing or even eliminating proteinuria in WT1 MAN patients (8/9). 目的： 探讨WT1变异相关肾病临床、病理特点与基因变异类型的关系。 方法： 回顾性分析2009年1月—2018年5月南方医科大学南方医院、中山大学孙逸仙纪念医院、中山大学附属第一医院儿科新诊治及既往诊治的WT1变异相关肾脏病患儿的临床和病理特点，与WT1基因变异的相关性。 结果： 共诊治WT1变异相关肾脏病患儿20例（新诊治5例），男6例，女14例。（1）Denys-Drash综合征10例：发现蛋白尿的中位年龄为1岁7月龄。弥漫系膜硬化3例，微小病变4例，局灶节段肾小球硬化（FSGS）1例，2例无病理。2例见肾小球基底膜（GBM）显著弥漫增厚。钙神经素抑制剂（CNIs）治疗5例，3例完全缓解，2例部分缓解。8例肾功能仍正常。基因检查结果WT1错义变异6例，无义变异3例，移码变异1例。（2）Frasier综合征（FS）2例：发现蛋白尿的年龄分别为1岁1月龄和1岁9月龄；均为FSGS，GBM分层。分别在1岁6月龄和6岁6月龄进入终末期肾脏病（ESRD）。CNIs治疗1例，蛋白尿部分缓解。均为WT1基因剪切变异。（3）孤立性肾病8例：3例为剪切变异，其中1例5月龄发病已进入ESRD，FSGS 1例，微小病变1例，均见GBM分层；CNIs治疗，1例部分缓解，肾功能正常，1例无效，6岁9月龄进入ESRD。5例为错义变异；3例病理为弥漫系膜硬化的患儿，2例在6月龄即进入ESRD，1例9岁进入ESRD。 结论： Denys-Drash综合征病情进展慢。WT1基因变异相关肾病基因变异类型中错义变异为11/20，剪切变异为5/20，其中剪切变异相关肾病起病早、进展快，可见GBM分层。CNIs治疗有效降低尿蛋白（8/9）。.

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