title: Surgical management and genotype/phenotype correlations in WT1 gene-related diseases (Drash, Frasier syndromes).
abstract: OBJECTIVE
  The WT1 gene plays a role in urogenital and gonadal development. Germline mutations of this gene have been observed in patients with Drash or Frasier syndrome (Sd). The purpose of this report is to compare phenotype and genotype of these patients.
  
  
  METHODS
  Retrospective study of 12 patients treated since 1980 for WT1 gene-related disorders was conducted.
  
  
  RESULTS
  End-stage renal disease (ESRD) occurred in 9 patients, mostly because of diffuse mesangial sclerosis (DMS) or focal and segmental glomerular sclerosis (FSGS). Seven patients underwent kidney transplantation, and 2 died. Eleven tumors occurred: 8 Wilms' tumors, one soft tissue tumor, one bladder papilloma, and one gonadoblastoma. Wilms' tumors occurred at a younger age than expected. Eight patients had a 46,XY karyotype. One of these XY patients had female phenotype (Frasier syndrome); she was raised as a girl with bilateral gonadectomy. Seven XY patients had ambiguous phenotype; 4 have been raised as boys and 3 as girls. Four patients had a 46,XX karyotype; they had female genitalia and were raised as girls. WT1 gene analysis was performed in 10 patients and showed heterozygous germline mutations in exon 9 (n = 6), intron 9 (n = 1), exon 3 (n = 1), exon 4 (n = 1), or exon 7 (n = 1).
  
  
  CONCLUSIONS
  ESRD was secondary to DMS when exon 9 was mutated, and secondary to FSGS when intron 9 was mutated. When exon 3, 4, and 7 were mutated, no nephropathy has been observed. Wilms' tumors occurred with any kind of WT1 mutation except intron 9. Abnormal sexual differentiation has been observed in all XY patients with WT1 mutation, and the most profound inversion of phenotype was observed with mutation in intron 9. Correlation between phenotype and genotype provides better understanding of the role of WT1, and can help the surgeon in the management of these patients.
authors.affiliation: Hôspitale des Malades, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Auber
authors.forename: S
authors.initials: S
authors.lastname: Lortat-Jacob
authors.forename: S
authors.initials: S
authors.lastname: Sarnacki
authors.forename: F
authors.initials: F
authors.lastname: Jaubert
authors.forename: R
authors.initials: R
authors.lastname: Salomon
authors.forename: E
authors.initials: E
authors.lastname: Thibaud
authors.forename: C
authors.initials: C
authors.lastname: Jeanpierre
authors.forename: C
authors.initials: C
authors.lastname: Nihoul-Fékété
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D030321:Denys-Drash Syndrome / Q000235:genetics* / Q000601:surgery*; D005260:Female; D016162:Genes, Wilms Tumor; D005838:Genotype; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms / Q000235:genetics / Q000601:surgery; D008297:Male; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D012732:Sex Determination Analysis; D012733:Sex Differentiation