Denys-Drash Syndrome 

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

Overview

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. See the image below.

Gross nephrectomy specimen shows a Wilms tumor pus Gross nephrectomy specimen shows a Wilms tumor pushing the normal renal parenchyma to the side.

See Wilms Tumor: A Pediatric Oncology Success Story, a Critical Images slideshow, to help identify the clinical features, staging evaluation, prognostic factors, and therapeutic options for this disease.

The characteristic nephropathy in Denys-Drash syndrome is termed diffuse mesangial sclerosis.[1] This condition clinically manifests as an early onset nephrotic syndrome and progresses to renal failure during the first 3 years of life. Among the intersex disorders, pure gonadal dysgenesis with male pseudohermaphroditism is the classic presentation, although a wide variety of abnormalities in gonadal differentiation can be encountered.

Pathophysiology

Denys-Drash syndrome is the result of mutations in the WT1 gene on chromosome band 11p13.[2, 3, 4, 5] 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.

Epidemiology

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.[6, 7, 8] New cases are being reported worldwide.[9]

Mortality/Morbidity

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

  • 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-, sex-, and age-related demographics

Denys-Drash syndrome has no race predilection.

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.

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.

Prognosis

All patients develop nephropathy and progress to ESRD within 2 years from the diagnosis or before age 3 years.

Virtually all patients with Denys-Drash syndrome who have their native kidneys develop Wilms tumor. Patients with unilateral Wilms tumor are at risk for contralateral tumor. Staging and histologic criteria are prognostic in patients with Wilms tumor.

Patient Education

Provide genetic counseling.

Explain role of prophylactic surgery to prevent Wilms tumor and gonadoblastoma.

Explain renal replacement therapy options, including renal transplantation.

 

Presentation

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 include the following:

  • 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. Note the following:

  • 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.

Complications

Potential complications for Denys-Drash syndrome include the following:

  • Patients with nephrotic syndrome may encounter recurrent infections, nutritional deficiencies, and, occasionally, venous thrombosis. Progression to end-stage renal disease (ESRD) is inevitable.

  • Complications of chemotherapy include life-threatening infections and secondary malignancies.

  • The risk for Wilms tumor development in any residual renal tissue and for gonadoblastoma in dysgenetic gonads is high.

 

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

 

Workup

Laboratory Studies

Consider the following laboratory studies:

  • Urinalysis: Proteinuria is the hallmark of the nephropathy in Denys-Drash syndrome (DDS) and is usually in the nephrotic range. Hematuria (gross or microscopic) may also be revealed.

  • Renal function tests: BUN and serum creatinine levels may be within reference ranges in the early stages of Denys-Drash syndrome but worsen with advancing nephropathy or development of bilateral Wilms tumor. End-stage renal disease (ESRD) development is accompanied by hyperkalemia and hyperphosphatemia.

  • Wilms tumor markers: Increased levels of hyaluronic acid, hyaluronic acid-stimulating activity, erythropoietin, and renin prohormone are associated with Wilms tumor.

  • Chromosome analysis: Obtain karyotype determination in all patients with suspected Denys-Drash syndrome, even in the absence of ambiguous genitalia. Analysis of band 11p13 and determination of the WT1 mutation is important in all patients with the nephropathy of DDS, even in the absence of Wilms tumor or obvious intersex disorder. These findings confirm the genetic diagnosis and alert the physician to the significantly increased risk of Wilms tumor development.

Imaging Studies

Consider the following imaging studies:

  • Abdominal and pelvic ultrasonography: Perform ultrasonography in all patients who present with signs and symptoms that suggest Denys-Drash syndrome. At regular intervals after the initial diagnosis, continue evaluating the kidneys for the quality of renal parenchyma and for the presence of Wilms tumor. Screen all individuals for the presence of abnormal internal genitalia (eg, undescended testes, undifferentiated and/or streak gonads) because of their risk of developing a gonadoblastoma (both in 46,XY and 46,XX individuals).

  • Abdominal and pelvic CT scanning: This scan is a more sensitive test for revealing Wilms tumor, especially to reveal unsuspected contralateral tumor or metastases, to demonstrate invasion of contiguous structures, to predict surgical resectability, and to monitor response to chemotherapy and surgical resection.

  • Chest radiography: Radiography reveals pulmonary metastases.

Procedures

Biopsy is essential for the diagnosis of Denys-Drash syndrome because it confirms the presence of diffuse mesangial sclerosis. Obtain the kidney biopsy specimen by percutaneous biopsy in children without Wilms tumor at the time of presentation. In patients with Wilms tumor, obtain kidney tissue at the time of nephrectomy. Note the image below.

Gross nephrectomy specimen shows a Wilms tumor pus Gross nephrectomy specimen shows a Wilms tumor pushing the normal renal parenchyma to the side.

Histologic Findings

The pathognomonic kidney lesion is termed diffuse mesangial sclerosis. Features of the early phase include expansion of the glomerular mesangial matrix, obliteration of the capillary lumens, thickening of the glomerular basement membrane, and hypertrophy of the podocytes. Features of the late phase are mesangial matrix sclerosis, glomerular tuft contraction, prominent tubular atrophy, and interstitial fibrosis.

Wilms tumor originates from pluripotential cells of the metanephric blastema and consists of blastemal, stromal, and epithelial cells. The presence of anaplasia suggests a poor prognosis.

Multiple gonadal abnormalities have been described, including the following:

  • Streak ovary containing primordial follicles

  • Müllerian and wolffian ducts

  • Streak gonad with ovarian-type stroma lacking primordial follicles and with primitive canalicular seminiferous tubules

  • Dysgenetic or atrophic intraabdominal testes

 

Treatment

Medical Care

Cornerstones of Denys-Drash syndrome (DDS) medical therapy include management of fluid and electrolyte balance, treatment of hypertension, renal replacement therapy for patients with end-stage renal disease (ESRD) or after bilateral nephrectomy, and chemotherapy for patients with Wilms tumor.

Surgical Care

The management of Denys-Drash syndrome is challenging, and optimal management strategies have not been established. The plan must be guided by the typical early progression of diffuse mesangial sclerosis to end-stage renal disease (ESRD), high risk of Wilms tumor development, and highly variable clinical course.[10]

In patients without Wilms tumor at the time of Denys-Drash syndrome diagnosis, two management strategies have been proposed: radical and conservative. The radical approach involves prophylactic bilateral nephrectomy prior to ESRD progression in order to avoid development of Wilms tumor and shortened total duration of renal replacement therapy prior to transplantation.[11] The conservative approach involves close monitoring for Wilms tumor development using serial imaging studies.[12, 13] In patients who develop Wilms tumor, radical bilateral nephrectomy is advocated over nephron-sparing surgery to preserve renal function as long as possible.[14]

A 2018 survey of the international pediatric nephrology community described management of 21 confirmed cases of Denys-Drash syndrome.[15] The authors concluded that, based on the known risks associated with ESRD, the variable course of Denys-Drash syndrome, and the relatively good prognosis associated with Wilms tumor, the guiding principle of renal function preservation is most logical. Most surveyed would advocate bilateral prophylactic nephrectomy after ESRD is reached owing to the high tumor risk, which is likely further heightened after transplantation.

Surgical treatment of Wilms tumor should follow the guidelines of the National Wilms Tumor Study-4 and -5 Protocols.[16, 17]

Denys-Drash syndrome manifests as gonadal dysgenesis and increased risk of gonadal malignancy. According to the Chicago consensus and other published data, the incidence of gonadoblastoma in patients with 46-XY Denys-Drash is 40%.[18, 19] Gonadectomy versus close observation has been debated, although data supporting each approach are limited. In 2019, two patients who were managed conservatively experience delayed puberty owing to primary hypogonadism.[19] Hence, gonadal preservation does not provide endocrinological benefit while risking the development of gonadal malignancy.

Kidney transplantation is the treatment of choice after bilateral nephrectomy. For patients with Wilms tumor, a 2-year period free of chemotherapy and tumor is recommended prior to renal transplantation.

Consultations

Consultations may be indicated with the following specialists:

  • Pediatric nephrologist - For managing the nephropathy, ESRD, hypertension, and medical aspects of transplantation

  • Pediatric oncologist - For diagnosis and treatment of Wilms tumor and gonadoblastoma

  • Pediatric surgeon - For managing Wilms tumor, access in renal replacement therapy and surgical aspects of renal transplantation, and evaluation and possible removal of abnormal gonads

  • Pediatric endocrinologist - For evaluation and management of intersex disorders

  • Geneticist - For chromosomal analysis, molecular diagnosis, and genetic counseling

Diet

A low-sodium diet is important to manage hypertension and edema. Patients with renal insufficiency require a low-potassium, low-phosphate diet.

Further Outpatient Care

In patients with Denys-Drash syndrome (DDS), arrange for follow-up with a pediatric nephrologist for renal transplantation and for ongoing management of nephrotic syndrome, hypertension, and renal insufficiency.

Arrange for follow-up with a pediatric oncologist for ongoing management of Wilms tumor. The Children's Oncology Group has released guidelines for long-term follow-up.[20]

Arrange for follow-up with a pediatric endocrinologist for management of intersex disorders.

Transfer

Children with Denys-Drash syndrome require integrated interdisciplinary care, including such pediatric subspecialty services as nephrology, surgery, oncology, endocrinology, and genetics.

 

Medication

Medication Summary

The general medical therapy for the accompanying renal insufficiency, Hypertension, Nephrotic Syndrome, and Wilms Tumor are detailed in the respective chapters.