Frasier syndrome: A cause of focal segmental glomerulosclerosis in a 46,XXfemale

The description of Frasier syndrome until now has been restricted to XY fem ales with gonadal dysgenesis, progressive glomerulopathy, and a significant risk of gonadoblastoma. Mutations in the donor splice site in intron 9 of the Wilms' tumor (WT1) gene have been shown to cause Frasier syndrome and a re distinct from WT1 exon mutations associated with Denys-Drash syndrome. T he WT1 gene, which is essential for normal kidney and gonadal development, encodes a zinc finger transcription factor. The intron 9 alternative splice donor site mutation seen in Frasier syndrome leads to loss of three amino acids (+KTS isoform), thus disrupting the normal ratio of the +KTS/-KTS iso forms critical for proper gonadal and renal development. This study examine s two sisters with identical intron 9 mutations. The proband carries a clas sic diagnosis of Frasier syndrome with 46,XY gonadal dysgenesis, whereas he r sister has progressive glomerulopathy but a 46,XX karyotype and normal fe male development. This indicates that the proper WT1 isoform ratio is criti cal for renal and testicular development, but apparently does not affect ei ther ovarian development or function. It is proposed that the clinical defi nition of Frasier syndrome should be broadened to include 46,XX females wit h normal genital development and focal segmental glomerulosclerosis associa ted with a WT1 intron 9 donor splice site mutation. Nephrologists need to c onsider the possibility of this heritable syndrome in evaluation of females with focal segmental glomerulosclerosis and to consider their risk for gon adal malignancy, as well as the risk for kidney disease, gonadal dysgenesis , and malignancy in their offspring.