title: 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.affiliation: Centre for Kidney Research, Department of Nephrology, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Geoff Y
authors.initials: GY
authors.lastname: Zhang
authors.forename: Susan
authors.initials: S
authors.lastname: Arbuckle
authors.forename: Nicole
authors.initials: N
authors.lastname: Graf
authors.forename: Albert
authors.initials: A
authors.lastname: Shun
authors.forename: Martin
authors.initials: M
authors.lastname: Silink
authors.forename: Deborah
authors.initials: D
authors.lastname: Lewis
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
mesh_terms: D002648:Child; D030321:Denys-Drash Syndrome / Q000150:complications / Q000235:genetics; D016162:Genes, Wilms Tumor / Q000502:physiology*; D006801:Humans; D007223:Infant; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics / Q000601:surgery*; D008297:Male; D020125:Mutation, Missense; D009392:Nephrectomy / Q000379:methods*; D011230:Precancerous Conditions / Q000235:genetics / Q000601:surgery*; D009396:Wilms Tumor / Q000235:genetics / Q000601:surgery*