An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis.

The Wilms' tumor gene (WT1) encodes a zinc-finger transcription factor involved in the development of the kidneys and gonads and their subsequent normal function. Mutations in the WT1 gene were identified in patients with WAGR (Wilms' tumor, aniridria, genitourinary abnormalities, and mental retardation), Denys-Drash syndrome, and Frasier syndrome (FS). Constitutional heterozygous mutations of the WT1 gene, almost all located at intron 9, are found in patients with FS. This syndrome is characterized by female external genitalia in 46,XY patients, late renal failure, streak gonads, and high risk of gonadoblastoma development. We report a male with FS with an unusual phenotype characterized by normal penis size with perineal hypospadias, end-stage renal failure at the age of 19 yr, normal adult male serum T levels, extremely elevated gonadotropin levels, para-testicular leiomyoma, unilateral testicular germ cell tumor, bilateral gonadoblastoma, and absence of gonadal dysgenesis. Automatic sequencing identified the IVS9 +4C>T mutation in the WT1 gene, which predicts a change in splice site utilization. WT1 transcript analysis showed reversal of the normal positive/negative KTS (lysine, threonine, and serine) isoform ratio, confirming the diagnosis of FS. This patient with FS presents an external genitalia of Denys-Drash syndrome, suggesting that these two syndromes are not distinct diseases but may represent two ends of a spectrum of disorders caused by alterations in WT1 gene. This case expands the spectrum of phenotypes associated with WT1 mutations, by including predominantly male ambiguous genitalia and absence of gonadal dysgenesis, extremely high gonadotropin levels, and delayed adrenarche, and presence of a para-testicular leiomyoma, bilateral gonadoblastoma, and germ cell neoplasia.