eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Denys-Drash Syndrome

Author: Agnieszka Swiatecka-Urban, MD, FASN, Assistant Professor, Department of Pediatrics, Cell Biology and Physiology, University of Pittsburgh School of Medicine; Assistant Professor, Department of Nephrology, Children's Hospital of Pittsburgh
Coauthor(s): Prasad Devarajan, MD, Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, Chief Executive Officer of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Contributor Information and Disclosures

Updated: Apr 10, 2009

Introduction

Background

Denys-Drash syndrome (DDS) is a rare disorder consisting of the triad of congenital nephropathy, Wilms tumor, and intersex disorders resulting from mutations in the Wilms tumor suppressor (WT1) gene. Nephropathy is a constant feature; in the incomplete forms of the syndrome, the nephropathy is present with either Wilms tumor or intersex disorders, but the vast majority of patients with Denys-Drash syndrome are destined to develop Wilms tumor in any residual renal tissue.

Pathophysiology

Denys-Drash syndrome is the result of mutations in the WT1 gene on chromosome band 11p13.² The WT1 gene contains 10 exons that produce 4 different messenger RNAs (mRNAs) as a result of 2 alternative splicing sites in exons 5 and 9 that, in turn, encode 4 different isoforms of the WT1 protein. Splicing at the second alternative site (exon 9) is thought to have a great biological importance and results in the inclusion or exclusion of 3 amino acids, lysine, threonine, and serine (KTS), yielding the KTS-positive isoform when the amino acids are included and KTS-negative isoform when excluded. The precise ratio of the KTS-positive/negative isoforms seems to be crucial for the normal function of the WT1 gene.

The WT1 protein is a transcription factor predominantly expressed in the embryonic kidneys and gonads. Exons 1-6 of the WT1 gene encode the regulatory domain, which regulates expression of target genes, and exons 7-10 encode the 4 zinc fingers of the DNA-binding region of the WT1 protein. The WT1 protein mediates the mesenchymal-epithelial transition and differentiation during morphogenesis of the kidney and gonad by repressing genes that encode cell proliferation factors and by activating genes that encode markers of epithelial cell differentiation.

Point mutations in the WT1 gene result in loss of its regulatory function, with the consequent abnormalities in glomerular formation and gonadal differentiation seen in Denys-Drash syndrome. Mutations that disrupt the second alternative splicing site of the WT1 gene alter the normal ratio of KTS-positive/negative isoforms from 2:1 to 1:2 and result in abnormalities in glomerular formation and gonadal differentiation seen in Frasier syndrome. In striking contrast, complete deletions of band 11p13 result in the Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome, which is characterized by structural urinary tract abnormalities without nephropathy.

Frequency

International

The frequency of Denys-Drash syndrome is unknown. Worldwide, more than 200 cases of Denys-Drash syndrome have been reported since 1967 when Denys et al originally described a child with nephropathy, ambiguous genitalia, and Wilms tumor.

Mortality/Morbidity

Mortality and morbidity are high because of the natural history of the nephropathy and the high risk of malignancies.

• Nephropathy: Patients with Denys-Drash syndrome develop early-onset nephrotic syndrome, have a high prevalence of severe hypertension, and experience rapid progression to end-stage renal disease (ESRD).
• Malignancy: The vast majority of patients with Denys-Drash syndrome are destined to develop Wilms tumor in the native kidneys and are at significant risk for development of gonadoblastoma in the dysgenetic gonads.

Race

Denys-Drash syndrome has no race predilection.

Sex

Although both sexes can be affected, the presence of intersex disorders makes the estimation of the male-to-female ratio misleading because individuals with Denys-Drash syndrome who are assigned the female gender may be genotypic males (XY gonadal dysgenesis with female phenotype). Ascertainment is also biased toward children with ambiguous genitalia (males), whereas diagnosis in females may be delayed or not established.

Age

• Nephropathy: Nephrotic syndrome usually manifests in infants aged 2 weeks to 18 months. Progression to ESRD occurs within weeks to 2 years from the time of diagnosis or before the age of 3 years.
• Wilms tumor: Median age at discovery is 12.5 months in cases associated with Denys-Drash syndrome, as opposed to 36 months in patients with isolated Wilms tumor without Denys-Drash syndrome. The earliest tumor onset was in patients with truncation mutations (12 mo, 66 patients) compared with missense mutations (18 mo, 30 patients).
• Intersex disorders: These conditions usually manifest at birth.

Clinical

History

• Denys-Drash syndrome (DDS) symptoms related to nephropathy: Placental size, pregnancy, and delivery are usually normal. At onset (usually within the first year of life), typical symptoms are those of nephrotic syndrome (eg, edema, abdominal distention, recurrent infections). With the rapid decline of the glomerular filtration rate (GFR) and progression to ESRD, the following additional symptoms develop:
  • Decreased activity
  • Poor feeding and growth
  • Loss of developmental milestones
  • Nonspecific aches and pains
  • Oliguria
• Denys-Drash syndrome symptoms related to Wilms tumor: Palpable abdominal mass is the most common manifesting symptom, noticed in 90% of children by a physician on routine physical examination or by the parent during routine care. Other symptoms include the following:
  • Abdominal distention
  • Abdominal pain
  • Hematuria
  • Weight loss
  • Poor feeding
  • Inguinal hernia
  • Acute abdomen

Physical

• Signs related to nephropathy: At onset, signs of nephrotic syndrome predominate (eg, generalized edema, ascites). Evidence of venous thrombosis occasionally may develop secondary to nephrotic syndrome. With the decline of GFR, severe hypertension becomes apparent. Pallor reflecting anemia develops. When ESRD ensues, the following signs develop secondary to renal osteodystrophy:
  • Decreased activity
  • Loss of developmental milestones
  • Decline in the growth rate
  • Skeletal abnormalities (similar to those of vitamin D-deficient rickets)
• Signs related to Wilms tumor: A palpable abdominal mass, hematuria, and hypertension are the most common signs. Other findings may include the following:
  • Weight loss
  • Obstipation
  • Inguinal hernia
  • Acute surgical abdomen
  • Respiratory distress from pleural effusions
  • Signs of congestive heart failure (CHF)
• Signs related to intersex disorders
  • Most individuals with Denys-Drash syndrome who carry the 46,XY or 46,XX/46,XY karyotype have male pseudohermaphroditism. The spectrum of anomalies of the external genitalia may include penoscrotal hypospadias with cryptorchidism, enlarged clitoris with labial fusion, bifid scrotum with palpable gonads, and micropenis.
  • Abnormalities of the internal reproductive organs in these individuals may include presence of the vagina and uterus, streak ovaries, and dysgenetic testes. Individuals with the 46,XX karyotype may have streak gonads but usually display a normal phenotype and are considered to have the incomplete form of Denys-Drash syndrome.

Causes

• More than 96% of individuals with a clinical diagnosis of Denys-Drash syndrome have been found to carry a mutation in the WT1 gene. The vast majority of these mutations are missense changes in exons 9 or 8, which encode for the zinc fingers 3 and 2, respectively.
• The exon 9 amino acid, arginine-394, critical in the DNA binding activity of the WT1 protein, is considered a mutational hot spot for Denys-Drash syndrome. A mutation of arginine-394 was present in 14 of 30 patients with Denys-Drash syndrome in one review of the literature.
• Increasing number of mutations in other exons have been described. Another review identified missense mutations in 30 patients and mutations that lead to premature chain termination (truncation mutations) in 66 patients. Patients with truncation mutations had high frequency of bilateral Wilms tumor compared with patients with missense mutations (52% vs. 17%, respectively), with a higher percentage of bilateral tumors in patients with truncations that occurred in the 5' half of the WT1 gene. Such mutations result in a WT1 protein that lacks a functional nuclear localization signal.
• The mutant cytoplasmic WT1 protein is thought to sequester some of the wild-type WT1 protein in the cytoplasm, resulting in a reduced amount of nuclear WT1. Furthermore, other putative WT1 interacting partners may also be sequestered in the cytoplasm, where they cannot perform their normal function.
• Mutation in a single allele of the WT1 gene is sufficient to produce nephropathy and intersex disorder. One hypothesis suggests the abnormal WT1 allele product interacts with the function of the unaffected wild-type WT1 allele in a dominant-negative fashion and changes its normal regulatory functions.
• The vast majority of patients with Denys-Drash syndrome have male karyotype and present with a wide spectrum of gonadal abnormalities; conversely, individuals with Denys-Drash syndrome and female karyotype have less severe or no gonadal abnormalities.
  • In patients with 46,XY, the KTS-negative isoform of the WT1 protein associates and achieves synergy with steroidogenic factor 1 (SF1). SF1, in turn, promotes expression of the gene-encoding müllerian inhibiting substance (MIS).
  • In addition, DAX1, a gene that directs ovarian development, antagonizes this synergy. In the presence of the WT1 mutations characteristic in Denys-Drash syndrome, the abnormal WT1 protein cannot associate with SF1, and testis development fails because of the decreased expression of MIS and the unopposed action of the DAX1 gene.
  • The degree to which the synergy between WT1 and SF1 is interrupted determines the severity of gonadal abnormalities in 46,XY individuals. In contrast, in 46,XX individuals, an intact WT1 gene has not been shown absolutely necessary for normal female development; these patients have less severe or no gonadal abnormalities.
• Development of Wilms tumor in patients with Denys-Drash syndrome results from mutations in both alleles of the WT1 gene. According to the 2-hit genetic model, Wilms tumor is a consequence of 2 independent events that lead to loss of function of both alleles of the WT1 gene. A constitutional or germline mutation in a single allele of the WT1 gene (first hit) leads to persistence of an undifferentiated mesenchyme. A somatic mutation (second hit) or loss of heterozygosity in the second allele causes uncontrolled cell proliferation and Wilms tumor formation.

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