Denys-Drash Syndrome

A number sign (#) is used with this entry because Denys-Drash syndrome (DDS) is caused by heterozygous mutation in the WT1 gene (607102) on chromosome 11p13.

See also Meacham syndrome (608978) and Frasier syndrome (136680), allelic disorders with similar clinical features.

Mutation in the WT1 gene can also cause isolated nephrotic syndrome (NPHS4; 256370) and isolated Wilms tumor (194070).

Clinical Features

Drash et al. (1970) reported 2 unrelated children with a syndrome comprising pseudohermaphroditism, Wilms tumor, hypertension, and degenerative renal disease. Barakat et al. (1974) reported 3 cases of pseudohermaphroditism, nephron disorder, and Wilms tumor, and made reference to 2 additional unreported cases.

Habib et al. (1985) reported 10 children with features of Drash syndrome. All presented with nephropathy due to diffuse mesangial sclerosis before 2 years of age. Three patients also had male pseudohermaphroditism, 2 also had Wilms tumor, and 5 had all 3 features. Nine patients progressed to chronic or end-stage renal failure within a few months to 2 years from the onset; the tenth was in advanced renal failure at 11 years of age. Habib et al. (1985) proposed that the phenotype of Drash syndrome includes patients who have either Wilms tumor or pseudohermaphroditism, with the common denominator being early-onset nephropathy with distinctive glomerular lesions. These associations suggested an antenatal dysgenetic process.

Turleau et al. (1987) reported partial androgen receptor (AR; 313700) deficiency and mixed gonadal dysgenesis in a patient with Drash syndrome.

Friedman and Finlay (1987) noted that the sexual abnormality in Drash syndrome is male pseudohermaphroditism, or XY gonadal dysgenesis. In addition, renal failure or Wilms tumor may also develop late. The authors presented a patient without ambiguous genitalia, and suggested that all girls with Wilms tumor should be considered at risk for the Drash syndrome.

Moorthy et al. (1987) suggested that some of the patients reported as cases of Drash syndrome in fact had Frasier syndrome (136680). Moorthy et al. (1987) discussed 6 previously reported patients with streak gonads, pseudohermaphroditism, and renal failure. In several of the patients the diagnosis was established only after a successful kidney transplantation during evaluation for primary amenorrhea. Gonadoblastoma arising from the streak gonad was noted in 5 of the 6 patients.

Jadresic et al. (1990) reported 12 children with complete and incomplete forms of Drash syndrome. The common denominator was a nephropathy. Four had the full triad, consisting of nephropathy, Wilms tumor, and genital abnormalities; 5 had nephropathy and genital abnormalities, and 3 had nephropathy and Wilms tumor. Eight of 11 children with proteinuria had the nephrotic syndrome. Of the 10 whose condition progressed to end-stage renal failure, 7 were less than 3 years of age. The histologic features of Wilms tumor were favorable in all 7 children, and the tumor was bilateral in 3. Of the 9 patients who had genital abnormalities, 8 had 46,XY karyotype and either ambiguous genitalia (6) or normal female phenotype (2). One other patient had a normal 46,XX female karyotype and phenotype but had both mullerian and wolffian structures and a streak ovary. Nine patients had a distinct pelvicaliceal abnormality not previously reported as a feature of this syndrome. Other congenital abnormalities were aniridia, mental retardation, deafness, nystagmus, and cleft palate. Jadresic et al. (1990) concluded that Drash syndrome must be considered in any infant with unexplained nephropathy, particularly in young phenotypic female infants and in those children with ambiguous genitalia or Wilms tumor with an early presentation.

Devriendt et al. (1995) described a newborn with male pseudohermaphroditism and glomerular lesions but without Wilms tumor, who had a constitutional heterozygous WT1 mutation (R366H; 607102.0004). The child also had a large diaphragmatic hernia, a previously undescribed feature of Denys-Drash syndrome. The expression of the WT1 gene in pleural and abdominal mesothelium and the occurrence of diaphragmatic hernia in transgenic mice with a homozygous WT1 deletion strongly suggested that the diaphragmatic hernia in this patient was part of the malformation pattern caused by the WT1 mutation.

Schumacher et al. (1998) identified WT1 mutations in 10 children with early-onset nephrotic syndrome. Two genotypically female girls had isolated congenital/infantile nephrotic syndrome (NPHS4; 256370). Seven other patients, all of whom were genotypic males, had additional urogenital features consistent with DDS, such as uterus/vagina, ambiguous genitalia, or micropenis. The eighth child, a genotypic female, developed Wilms tumor at age 18 months, and was thus classified as having incomplete DDS. Renal biopsy showed diffuse mesangial sclerosis in 8 patients and focal segmental glomerulosclerosis in 2. End-stage renal disease was reached either concomitantly or within 4 months after onset of nephrotic syndrome in 7 patients. Four children developed Wilms tumor either before or concomitant with nephrotic syndrome. No WT1 mutations were found in 7 other children with isolated nephrotic syndrome who appeared to have a slower progression than the first group and who did not have Wilms tumor. Schumacher et al. (1998) proposed that patients with early-onset, rapidly progressive nephrotic syndrome and diffuse mesangial or focal segmental glomerulosclerosis on renal biopsy should be tested for WT1 mutations to identify those at risk for developing Wilms tumor.

Antonius et al. (2008) reported a patient with Denys-Drash syndrome who was found to have a left-sided congenital diaphragmatic hernia by ultrasound at 23 weeks' gestation. The pregnancy was complicated by oligo- and anhydramnios. At birth, the baby showed normal female genitalia without dysmorphic features and a 46,XY karyotype. There was severe respiratory insufficiency and pulmonary hypertension and the baby died at age 16 hours. Postmortem total body MRI showed double uterus with duplicated cervix and enlarged kidneys with abnormal cortex/medulla differentiation. There were no visible gonads. Genetic analysis identified the R366H mutation in the WT1 gene.

Mapping

In a patient with Drash syndrome, including bilateral Wilms tumor and gonadoblastoma, Dao et al. (1987) found tumor-specific loss of heterozygosity for markers on chromosome 11p, as in other types of Wilms tumor.

In 1 of 10 patients with Drash syndrome, Jadresic et al. (1991) found a deletion of region 11p13-p12, the only detectable autosomal chromosome abnormality in any of the patients studied. The authors concluded that deletions or major rearrangements of chromosome 11p13 are uncommon in patients with Drash syndrome.

Molecular Genetics

In 10 patients with Denys-Drash syndrome, Pelletier et al. (1991) identified mutations in the WT1 gene (607102.0003-607102.0006). Baird et al. (1992) demonstrated heterozygous constitutional mutations in 6 of 8 patients with the Denys-Drash syndrome. The mutations were the same as those identified by Pelletier et al. (1991). Clinical features of 6 patients had previously been described by Jadresic et al. (1990).

Hastie (1992) reviewed the evidence showing that dominant-negative mutations in the WT1 gene cause Denys-Drash syndrome and noted that this proves that the WT1 tumor suppressor gene plays a crucial role in normal genitourinary development.

Mueller (1994) reviewed the Denys-Drash syndrome in detail on the basis of 150 reported cases. A tabulation was provided of 25 reported mutations in the WT1 gene.

Nomenclature

Garfunkel (1985) suggested the eponym 'Denys-Drash syndrome' because the constellation of anomalies was first described by Denys et al. (1967) in the French literature.

Animal Model

Patek et al. (1999) reported that heterozygosity for a Wt1 mutation that truncated zinc finger-3 at codon 396 induced DDS in heterozygous and chimeric mice. Patek et al. (2003) further showed that Wt1 mutant mouse cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells. The development of glomerulosclerosis was preceded by widespread loss of Zo1 (601009) signal in podocytes, increased intrarenal renin (179820) expression, and de novo podocyte TGF-beta-1 (190180) expression, but not podocyte Pax2 expression or loss of Wt1, synaptopodin (608155), alpha-actinin-4 (604638), or nephrin (602716) expression. However, podocytes in partially sclerotic glomeruli that still expressed WT1 at high levels showed reduced vimentin (193060) expression, cell cycle reentry, and reexpressed desmin (125660), cytokeratin (139350), and Pax2. The authors suggested that (i) glomerulosclerosis may not be due to loss of WT1 expression by podocytes; (ii) podocyte PAX2 expression may reflect reexpression rather than persistent expression, and may be the consequence of glomerulosclerosis; (iii) glomerulosclerosis may be mediated systemically and the mechanism may involve activation of the renin-angiotensin system; and (iv) podocytes may undergo typical maturational changes but subsequently dedifferentiate and revert to an immature phenotype during disease progression.

Defects in the WT1 gene are thought to modify the crosstalk between podocytes and other glomerular cells and ultimately lead to glomerular sclerosis, as observed in diffuse mesangial sclerosis (DMS). To identify podocyte WT1 targets, Ratelade et al. (2010) generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli, and identified candidates that may modify podocyte differentiation and growth factor signaling in glomeruli. Sciellin (SCEL; 604112) and Sulf1 (610012), which encodes a 6-O-endosulfatase, were expressed in wildtype podocytes and strongly downregulated in mutants. Coexpression of Wt1, Scel, and Sulf1 was found in a mesonephric cell line, and siRNA-mediated knockdown of WT1 decreased Scel and Sulf1 mRNAs and proteins. ChIP assay showed that Scel and Sulf1 were direct WT1 targets. Cyp26a1 (602239), encoding an enzyme involved in the degradation of retinoic acid, was upregulated in mutant podocytes. Ratelade et al. (2010) noted that CYP26A1 may play a role in the development of glomerular lesions but does not seem to be regulated by WT1.