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Denys-Drash Syndrome: Differential Diagnoses & Workup

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

Differential Diagnoses

Nephrotic Syndrome
WAGR Syndrome
Wilms Tumor

Other Problems to Be Considered

  • 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.
  • Other renal tumors

Workup

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

  • 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.

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

More on Denys-Drash Syndrome

Overview: Denys-Drash Syndrome
Differential Diagnoses & Workup: Denys-Drash Syndrome
Treatment & Medication: Denys-Drash Syndrome
Follow-up: Denys-Drash Syndrome
Multimedia: Denys-Drash Syndrome
References
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References

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Further Reading

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Keywords

Denys-Drash syndrome, Drash syndrome, DDS, Wilms tumor, intersex disorder, congenital nephropathy, end-stage renal disorder, ESRD, diffuse mesangial sclerosis, nephrotic syndrome, pseudohermaphroditism, gonadoblastoma, oliguria, generalized edema, ascites, hypertension, anemia, rickets, abdominal mass, penoscrotal hypospadias, cryptorchidism, enlarged clitoris with labial fusion, bifid scrotum with palpable gonads, micropenis

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Contributor Information and Disclosures

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
Agnieszka Swiatecka-Urban, MD, FASN is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Women in Nephrology
Disclosure: Nothing to disclose.

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
Prasad Devarajan, MD is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Leonard G Feld, MD, PhD, MMM, FAAP, Sara H Bissell and Howard C Bissell Endowed Chair in Pediatrics, Chief Medical Officer, Levine Children's Hospital, Carolinas Medical Center
Leonard G Feld, MD, PhD, MMM, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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