FaCD Online Syndrome Fact Sheet

Last updated: 21 Feb 2008

Name: Denys-Drash syndrome

Synonym: incl.: Early Onset Nephrotic Syndrome-WT1 associated

Mode of Inheritance: de novo / AD

Genes

WT1, mapped to 11p13

Tumor features

ovarian gonadoblastoma
testicular gonadoblastoma
Wilms' tumor (nephroblastoma)

Non-tumor features

ambiguous external genitals in 46,XX
ambiguous external genitals in 46,XY
ambiguous internal genitals in 46,XX
ambiguous internal genitals in 46,XY
hypospadia
male (46,XY) pseudohermaphroditism
nephropathy

Comment

Clinical hallmarks of DDS are ambiguous external and internal genitalia, Wilms tumor (bilateral in 20 %) and glomerulopathy (usually presenting in the first year). Gonadoblastoma (often bilateral) has been reported in a small subset of patients. [1]. Several clinical variants of DDS have been reported. The majority of DDS patients have a normal 46,XY karyotype (underdiagnosis/underreportation in 46,XX ?). Germline mutations in WT1 underlie DDS[2]. Most of these mutations arise de novo, however a familial case of a germline WT1 mutation present in a asymptomatic father as well as his son with DDS has been reported[3]. Early onset, rapidly progressive, nephrotic syndrome may be associated with germline WT1 mutations as well and these individuals may be at risk to develop Wilms tumor[4,5]. There is a clinical overlap with Frasier syndrome. DDS patients demonstrate diffuse mesangial sclerosis (DMS), whereas focal and segmental glomerulosclerosis (FSGS) is seen in FS patients. Both conditions should be regarded as part of the spectrum associated with germline WT1 mutations.

References

[1] Mueller RF. The Denys-Drash syndrome. J Med Genet 1994; 31(6):471-477.
[2] Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D. Germline mutations in the Wilm's tumor suppressor gene are associated with abnormal urogenital development in denys-drash syndrome. Cell 1991; 67:437-447.
[3] Coppes MJ, Liefers GJ, Higuchi M, Zinn AB, Balfe JW, Williams BRG. Inherited WT1 mutation in Denys-Drash syndrome. Cancer Res 1992; 52:6125-6128.
[4] Schumacher V, Scharer K, Wuhl E, Altrogge H, Bonzel KE, Guschmann M, Neuhaus TJ, Pollastro RM, Kuwertz-Broking E, Bulla M, Tondera AM, Mundel P, Helmchen U, Waldherr R, Weirich A, Royer-Pokora B. Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int 53[6], 1594-1600. 1998.
[5] Royer-Pokora B, Beier M, Henzler M, Alam R, Schumacher V, Weirich A, Huff V. Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. American journal of medical genetics. Part A 2004; 127(3):249-57.