Stallmach T, Neuhaus T J, Kösters R, Hailemariam S
Departement Pathologie, Universität Zürich.
Pathologe. 1998 May;19(3):230-4. doi: 10.1007/s002920050279.
About 10% of all nephroblastomas (Wilms' tumor) present as part of malformation syndromes. The Denys-Drash syndrome (DDS) comprises pseudohermaphroditism, glomerulopathy and, early, often bilateral Wilms' tumors. A nephrectomy was performed in a 4-month-old girl because of a Wilms' tumor. Two months later, low serum albumin levels and proteinuria had developed. A biopsy from the remaining kidney showed a glomerulopathy which could also be seen in the nephrectomy specimen. The morphology was highly characteristic: the innermost layer of the kidney cortex exhibited augmentation of the mesangial matrix only; the intermediate layer showed severe sclerosis of glomeruli with deposition of fibrillary material; and the subcapsular layer revealed very small glomeruli and atrophic tubuli. Fifteen months later, peritoneal dialysis was necessary and due to the high risk of tumor development in the remaining kidney, a nephrectomy was performed. Molecular analysis revealed a point mutation within exon 9 of the WT1 gene (394 ARG-->TRP), which was homozygous in the tumor and heterozygous within renal parenchyma. The DDS is caused by a mutation in the WT1 gene on chromosome 11p13 which occurs during oogenesis or spermiogenesis. The WT1 gene is highly expressed during the development of the genitalia and the kidney; damage in one allele only causes the malformation syndrome. Loss of the second allele of the WT1 gene constitutes the second step of tumorigenesis. The appearance of Wilms' tumors derived from cells homozygous for the mutation reveals the function of the WT1 gene as a tumor suppressor gene.
所有肾母细胞瘤（威尔姆斯瘤）中约10%表现为畸形综合征的一部分。迪尼-德拉斯综合征（DDS）包括假两性畸形、肾小球病，且早期常为双侧威尔姆斯瘤。一名4个月大的女孩因威尔姆斯瘤接受了肾切除术。两个月后，出现了低血清白蛋白水平和蛋白尿。对剩余肾脏进行活检显示存在肾小球病，在肾切除标本中也可见到。其形态极具特征性：肾皮质的最内层仅表现为系膜基质增多；中间层显示肾小球严重硬化并伴有纤维状物质沉积；而被膜下层可见非常小的肾小球和萎缩的肾小管。15个月后，需要进行腹膜透析，由于剩余肾脏发生肿瘤的风险很高，遂进行了肾切除术。分子分析显示WT1基因第9外显子内存在一个点突变（394 ARG→TRP），该突变在肿瘤中为纯合子，在肾实质中为杂合子。DDS由11p13染色体上WT1基因的突变引起，该突变发生在卵子发生或精子发生过程中。WT1基因在生殖器和肾脏发育过程中高度表达；仅一个等位基因受损就会导致畸形综合征。WT1基因第二个等位基因的缺失构成肿瘤发生的第二步。源自该突变纯合细胞的威尔姆斯瘤的出现揭示了WT1基因作为肿瘤抑制基因的功能。
