Sun L Z, Wang H Y, Li M, Lin H R, Wu J L, Tang W, Li Y J, Yue Z H, Liu T, Chen H M, Hu M Y
Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Zhonghua Er Ke Za Zhi. 2018 Oct 2;56(10):769-774. doi: 10.3760/cma.j.issn.0578-1310.2018.10.010.
To explore the clinical and pathological features and mutational types and their relations with WT1 mutation-associated nephropathy (WT1MAN). 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. 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. 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).
探讨WT1突变相关肾病（WT1MAN）的临床病理特征、突变类型及其相互关系。分析了南方医科大学南方医院、中山大学孙逸仙纪念医院和中山大学附属第一医院近十年间我们新收治并报道的病例的临床病理资料及WT1突变分析结果。共纳入20例患者（男6例，女14例），其中新诊断病例5例。（1）10例患儿诊断为Denys-Drash综合征（DDS）：蛋白尿中位起病年龄为1岁7个月。3例表现为弥漫性系膜硬化（DMS），4例为微小病变（MCD），1例为局灶节段性肾小球硬化（FSGS）；另外2例未行肾病理检查。2例观察到肾小球基底膜（GBM）增厚。5例应用钙调神经磷酸酶抑制剂（CNIs），3例蛋白尿完全缓解，另2例部分缓解。基因分析显示，6例为WT1错义突变，3例为无义突变，1例为移码突变。（2）2例诊断为Frasier综合征（FS）：蛋白尿分别于1岁1个月和1岁9个月时出现。2例均表现为伴有GBM分层的FSGS。分别于1岁6个月和6岁6个月时进展为终末期肾病（ESRD）。1例应用CNIs后蛋白尿部分缓解。2例患者均检测到WT1剪接突变。（3）8例为孤立性肾病（IN）：3例为剪接突变，5例为错义突变。3例剪接突变患者中，1例于5个月时出现肾病和肾衰竭。另外2例（1例为FSGS，另1例为MCD）均有GBM分层。二者均应用了CNIs，1例于14岁时蛋白尿部分缓解且肾功能正常；另1例无效，于6岁9个月时进入ESRD。5例错义突变患者中，3例为DMS，其中2例在6个月内进入ESRD，另1例DMS患者于9岁时进入ESRD。1例FSGS患者应用CNIs后完全缓解。DDS患者中观察到肾病进展缓慢（7/10）。错义突变（11/20）是该组患者中最常见的WT1变异类型，其次为剪接突变（5/20）。剪接突变患者中观察到肾病起病早（4/5）、进展快（4/5）和GBM分层（4/4）。CNIs对WT1 MAN患者减少甚至消除蛋白尿有效（8/9）。
