Denys-Drash syndrome (DDS)

2015-12-01   Maria Piccione , Emanuela Salzano 

Department of Sciences for Health Promotion and Mother and Child Care G. DAlessandro, University of Palermo, Palermo, Italy.;



Denys-Drash syndrome (DDS)


Drash syndrome , Wilms tumor and pseudo- or true hermaphroditism , Nephropathy, Wilms tumor, and genital anomalies


Meacham Syndrome(OMIM # 608978) is an allelic disorder with some clinical features overlapping plus cardiac and pulmonary malformations.


To date about 150 patients with DDS have been described and its prevalence is largerly unknown (Mueller 1994). The inheritance pattern is autosomal dominant, but most reported cases resulted from a de novo mutation in germline cells or in earlier phases of embryonic development as postzygotic somatic event (Coppes et al.1992).


220 Denys-Drash syndrome








Phenotype and clinics

Denys-Drash is a rare condition characterized by the triad of 46,XY disorder of sex developmental, renal dysfunction and Wilms Tumor. Litterature also described patients with complete and incomplete forms of Drash syndrome depending on the expression of a full or patial phenotype in which nephrophay is associated with either one of the other features (Jadresic et al.1990).
Male: 46, XY disorder of sex developmental with gonadal dysgenesis (sometimes both testicular and ovarian tissue present)inappropriate to drive a normal external genitalia development; higher risk to develop gonadoblastoma.
Female: gonadal dysgenesis with ambiguous genitalia; sometimes can present normal external genitalia; higher risk to develop gonadoblastoma (Koziell et al. 1999; Öçal G 2011).
Progressive diffuse mesangial sclerosis,focal glomerular sclerosis, nephrotic syndrome, highly progressive renal failure; nephroblastoma (Niaudet et al.2006).
Cardiovascular System
Secondary hypertension

Differential diagnosis

Frasier Syndrome
Denys-Drash Syndrome shares several clinical features with Frasier Syndrome so that has been proposed as another end of the WT1 mutations spectrum. Patients affected by Frasier Syndrome present a 46,XY partial gonadal dysgenesis with streak gonads and normal external genitalia (with uterus) associated more frequently with development of gonadoblastoma.
Glomerular damage consists usually in a non specific and focal sclerosis resulting in proteinuria and nephrotic syndrome that usually progresses to end -stage renal failure during adolescence or adulthood. Wilms tumor is not as common as in Denys-Drash Syndrome (Barbaux et al. 1997; Koziell et al. 1999)
Atlas Image
Comparison between Denys-Drash and Frasier Phenotypes.

Neoplastic risk

Most patients with DDS delevop Wilms tumor at the mean age of 18 months (vs a mean age of 44 months in sporadic Wilms tumor) with a bilateral onset in 20% of cases. Gonadoblastomas arise in dysgenetic gonads more frequently in Frasier Syndrome patients than DDS patients and usually present as benign tumors (Barbaux et al. 1997; Koziell et al. 2000).


Nephrophaty is usually poorly responsive to common treatments. Some patients with Frasier Syndrome have underwent bilateral surgical gonadectomy (Niaudet et al.2006).


Death is usually secondary to renal failure. In Denys-Drash Syndrome nephrophaty has an early onset and renal failure comes within 3 years, while a slower end-stage progression is typical of Frasier nephrophaty.
Rare reported patients with congenital diaphragmatic hernia died by average age of 24 hours (Antonius et al.2008).



Deletion or chromosomal rearrangements of 11p13 critical region are rarely reported: only 1 DDS case was found carrier of 11p13-p12 deletion and none with Frasier Syndrome (Jadresic et al.1991). However cytogenetic deletion involving 11p11 and 11p13 are described in sporadic Wilms Tumor and in Wilms tumor in association to WAGR (Wilms tumor, aniridia, genitourinary anomalies and mental retardation) Syndrome (OMIM #194072).

Genes involved and Proteins


Denys-Drash syndrome


Frasier syndrome


Meacham syndrome


Mesothelioma, somatic


Nephrotic syndrome, type 4


Wilms tumor, type 1



WT1 mediates trascriptional activation and\/or repression of several gene targets. It particular seems to directly synergize with SF1 participating to steroidogenesis and in sexual differentiation by regulating expression of the polypeptide hormone mullerian inhibiting substance. In addition WT1 plays a key role in podocyte gene-expression and subsequently in podocyte differentiation (Nachtigat et al 1998; Lefebvre et al. 2015).


Denys-Drash WT1 mutations are clustered particularly in the exons encoding Zf2 and Zf3in and behave as dominant negatives. Most WT1 mutations in rasier patients affect the exon 9 donor splice site resulting in a functional imbalance of WT1 +KTS isoforms, as detected on dysgenetic gonads by RTPCR (Klam et al.1998; Haber et al.1991). In addition transcriptional profiling of mice lacking the WT1 alternative splice isoform (+KTS) seems to have a more restrictive podocyte set of genes whose expression depends on these alternatively spliced isoforms (Klamt et al 1998; Lefebvre et al. 2015).

To be noted


http:\/\/\/kliniken-institute\/kliniken\/kinder-und-jugendmedizin\/ Registry for Patients with WT1 Mutation Associated Diseases - UKE - Universitätsklinikum Hamburg-Eppendorf; Klinik und Poliklinik für Kinder- und Jugendmedizinhttps:\/\/\/web\/Het-AMC\/Afdelingen\/Overzicht\/Klinische-Informatiekunde-KIK\/Klinische-Informatiekunde-KIK\/Department.htm ESPN\/ERA-EDTA Registry: European Registry for Children on Renal Replacement Therapy AMC - Academisch Medisch Centrum- Afdeling Klinische Informatiekunde


http:\/\/\/cgi-bin\/ Gene WT1 (GeneCards)http:\/\/\/condition\/denys-drash-syndrome Denys-Drash syndrome (Genetic Home Reference)


Pubmed IDLast YearTitleAuthors
219113222011Current concepts in disorders of sexual development.Öçal G et al
182031542008Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G > A(Arg366His) mutation.Antonius T et al
93988521997Donor splice-site mutations in WT1 are responsible for Frasier syndrome.Barbaux S et al
21725001990Clinicopathologic review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome).Jadresic L et al
94994251998Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.Klamt B et al
259933182015Alternatively spliced isoforms of WT1 control podocyte-specific gene expression.Lefebvre J et al
95901781998Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.Nachtigal MW et al
169271062006WT1 and glomerular diseases.Niaudet P et al
13275251992Inherited WT1 mutation in Denys-Drash syndrome.Coppes MJ et al
16587871991Alternative splicing and genomic structure of the Wilms tumor gene WT1.Haber DA et al
107622962000Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy?Koziell A et al
80719741994The Denys-Drash syndrome.Mueller RF et al

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