Denys-Drash Syndrome Differential Diagnoses

Updated: Oct 30, 2019
  • Author: Agnieszka Swiatecka-Urban, MD, FASN, FAAP; Chief Editor: Maria Descartes, MD  more...
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DDx

Diagnostic Considerations

Frasier syndrome

Frasier syndrome is phenotypically similar to Denys-Drash syndrome (DDS), with some notable differences, and both are caused by mutations in the WT1 gene. Frasier syndrome consists of nephrotic syndrome, complete XY gonadal dysgenesis, and increased susceptibility to gonadal tumors, usually gonadoblastomas. The nephropathy of Frasier syndrome usually is focal segmental glomerulosclerosis, as opposed to diffuse mesangial sclerosis seen in Denys-Drash syndrome. Nephropathy usually is relentless but leads to end-stage renal disease (ESRD) in late childhood, unlike patients with Denys-Drash syndrome for whom ESRD typically ensues by age 3 years.

Frasier syndrome is caused by specific mutations in the WT1 gene that disrupt the alternative splicing site in intron 9, unlike the mutations near or within the zinc-finger coding region characteristic for Denys-Drash syndrome. Also contrasting with Denys-Drash syndrome, in which WT1 mutations cause dysfunctional proteins, the mutations seen in Frasier syndrome produce normal WT1 proteins but alter the normal ratio of the KTS-positive/negative isoforms from 2:1 to 1:2.

These mutations demonstrate that a correct ratio of the WT1 isoforms is a critical requirement for normal development of the glomeruli and gonads. Patients with Frasier syndrome have no increased risk for Wilms tumor because the KTS-negative isoform of the WT1 protein retains its tumor suppressor function. The high risk of gonadoblastoma in patients with Frasier syndrome reflects the overall high risk of tumorigenesis in dysgenic gonads. Molecular mechanisms that underlie the intersex state and nephropathy in Frasier syndrome are poorly understood.

Differential Diagnoses