Prophylactic bilateral nephrectomies in two paediatric patients with missense mutations in the WT1 gene.

Abstract

BACKGROUND:

Denys-Drash syndrome (DDS) is associated with mutations of the Wilms' tumour 1 (WT1) gene, and is characterized by pseudohermaphroditism, a progressive glomerulopathy, and the development of Wilms' tumour. More than 90% of patients with DDS who carry constitutional intragenic WT1 mutations are at high risk (90%) for the development of Wilms' tumour. WT1 is a signalling protein with 90% of WT1 mutations occurring in the WT1 zinc finger region as single nucleotide polymorphisms, the majority of which are missense mutations.

METHODS:

Constitutional DNA was extracted from peripheral blood. Direct sequencing and restriction enzymes were employed to analyse mutations.

RESULTS:

Two children, 46XY males who had evidence of pseudohermaphroditism, hypogonadism and renal failure with a glomerulopathy atypical for DDS, but no Wilms' tumour or nephroblastomatosis, on investigation, prior to transplant, were identified with missense mutations in the WT1 gene, in exons 8 and 9, respectively. The decision to do prophylactic nephrectomies was based on the genetic identification of WT1 mutations supporting a diagnosis of incomplete DDS, with the potential for increased risk of malignancy with the development of Wilms' tumour. The nephrectomy specimens demonstrated nephrogenic rests (nephroblastomatosis), which have a potential for malignant transformation.

CONCLUSIONS:

WT1 missense mutations in exons 8 and 9 can be regarded as having the potential for malignant change supporting prophylactic nephrectomy in apparent incomplete DDS patients with end-stage renal disease.

• Authors: Min Hu, Geoff Y Zhang, Susan Arbuckle, Nicole Graf, Albert Shun, Martin Silink, Deborah Lewis, Stephen I Alexander
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 19 Issue 1 Pg. 223-6 (Jan 2004) ISSN: 0931-0509 [Print] England
• PMID: 14671061 (Publication Type: Case Reports, Journal Article)

Topics

• Child
• Denys-Drash Syndrome (complications, genetics)
• Genes, Wilms Tumor (physiology)
• Humans
• Infant
• Kidney Failure, Chronic (etiology, genetics)
• Kidney Neoplasms (genetics, surgery)
• Male
• Mutation, Missense
• Nephrectomy (methods)
• Precancerous Conditions (genetics, surgery)
• Wilms Tumor (genetics, surgery)