Guaragna Mara Sanches, Lutaif Anna Cristina Gervásio de Britto, Bittencourt Viviane Barros, Piveta Cristiane Santos Cruz, Soardi Fernanda Caroline, Castro Luiz Claudio Gonçalves, Belangero Vera Maria Santoro, Maciel-Guerra Andréa Trevas, Guerra-Junior Gil, Mello Maricilda Palandi De
Centro de Biologia Molecular e Engenharia Genética, Universidade Estadual de Campinas, Campinas, SP, Brazil.
Arq Bras Endocrinol Metabol. 2012 Nov;56(8):525-32. doi: 10.1590/s0004-27302012000800011.
Frasier syndrome (FS) is characterized by gonadal dysgenesis and nephropathy. It is caused by specific mutations in the Wilms' tumor suppressor gene (WT1) located in 11p23. Patients with the 46,XY karyotype present normal female genitalia with streak gonads, and have higher risk of gonadal tumor, mainly, gonadoblastoma. Therefore, elective bilateral gonadectomy is indicated. Nephropathy in FS consists in nephrotic syndrome (NS) with proteinuria that begins early in childhood and progressively increases with age, mainly due to nonspecific focal and segmental glomerular sclerosis (FSGS). Patients are generally unresponsive to steroid and immunosuppressive therapies, and will develop end-stage renal failure (ESRF) during the second or third decade of life. We report here four cases of FS diagnosis after identification of WT1 mutations. Case 1 was part of a large cohort of patients diagnosed with steroid-resistant nephrotic syndrome, in whom the screening for mutations within WT1 8-9 hotspot fragment identified the IVS9+5G>A mutation. Beside FS, this patient showed unusual characteristics, such as urinary malformation (horseshoe kidney), and bilateral dysgerminoma. Cases 2 and 3, also bearing the IVS9+5G>A mutation, and case 4, with IVS9+1G>A mutation, were studied due to FSGS and/or delayed puberty; additionally, patients 2 and 4 developed bilateral gonadal tumors. Since the great majority of FS patients have normal female external genitalia, sex reversal is not suspected before they present delayed puberty and/or primary amenorrhea. Therefore, molecular screening of WT1 gene is very important to confirm the FS diagnosis.
弗雷泽综合征（FS）的特征是性腺发育不全和肾病。它由位于11p23的威尔姆斯肿瘤抑制基因（WT1）的特定突变引起。核型为46,XY的患者表现为具有条索状性腺的正常女性生殖器，并且患性腺肿瘤的风险较高，主要是性腺母细胞瘤。因此，建议进行选择性双侧性腺切除术。FS中的肾病表现为肾病综合征（NS），伴有蛋白尿，蛋白尿在儿童早期开始出现，并随年龄增长而逐渐增加，主要是由于非特异性局灶节段性肾小球硬化（FSGS）。患者通常对类固醇和免疫抑制疗法无反应，并将在生命的第二个或第三个十年发展为终末期肾衰竭（ESRF）。我们在此报告4例经鉴定WT1突变后诊断为FS的病例。病例1是一大群被诊断为类固醇抵抗性肾病综合征的患者之一，在对WT1 8-9热点片段内的突变进行筛查时发现了IVS9 + 5G>A突变。除了FS，该患者还表现出异常特征，如泌尿系统畸形（马蹄肾）和双侧无性细胞瘤。病例2和病例3也携带IVS9 + 5G>A突变，病例4携带IVS9 + 1G>A突变，因FSGS和/或青春期延迟而接受研究；此外，患者2和患者4发生了双侧性腺肿瘤。由于绝大多数FS患者具有正常的女性外生殖器，在出现青春期延迟和/或原发性闭经之前不会怀疑性反转。因此，WT1基因的分子筛查对于确诊FS非常重要。
