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Denys-Drash Syndrome

  • Author: Agnieszka Swiatecka-Urban, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: May 27, 2014
 

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.

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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.

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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.

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.

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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 is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, Women in Nephrology

Disclosure: Received consulting fee from Mallinckrodt Pharmaceuticals for consulting.

Coauthor(s)

Prasad Devarajan, MD, FAAP Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of the Nephrology Fellowship Program, Medical Director of the Kidney Stone Center, Co-Director of the Institutional Office of Pediatric Clinical Fellowships, Director of Clinical Nephrology Laboratory, CEO of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine

Prasad Devarajan, MD, FAAP is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, Society for Pediatric Research

Disclosure: Received none from Coinventor on patents submitted for the use of NGAL as a biomarker of kidney injury for none.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

References
  1. Nso Roca AP, Pena Carrion A, Benito Gutierrez M, et al. Evolutive study of children with diffuse mesangial sclerosis. Pediatr Nephrol. 2009 May. 24(5):1013-9. [Medline].

  2. Andrade JG, Guaragna MS, Soardi FC, et al. Clinical and genetic findings of five patients with WT1-related disorders. Arq Bras Endocrinol Metabol. 2008 Nov. 52(8):1236-43. [Medline].

  3. da Silva TE, Nishi MY, Costa EM, et al. A novel WT1 heterozygous nonsense mutation (p.K248X) causing a mild and slightly progressive nephropathy in a 46,XY patient with Denys-Drash syndrome. Pediatr Nephrol. 2011 Aug. 26(8):1311-5. [Medline].

  4. Furtado LV, Pysher T, Opitz J, et al. Denys-Drash syndrome with neonatal renal failure in monozygotic twins due to c.1097G>A mutation in the WT1 gene. Fetal Pediatr Pathol. 2011. 30(4):266-72. [Medline].

  5. Guaragna MS, Soardi FC, Assumpcao JG, et al. The novel WT1 gene mutation p.H377N associated to Denys-Drash syndrome. J Pediatr Hematol Oncol. 2010 Aug. 32(6):486-8. [Medline].

  6. Breslow NE, Collins AJ, Ritchey ML, et al. End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol. 2005 Nov. 174(5):1972-5. [Medline].

  7. Children's Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Mar 2006. Available at http://www.survivorshipguidelines.org/.

  8. Al-Hussain T, Ali A, Akhtar M. Wilms tumor: an update. Adv Anat Pathol. 2014 May. 21(3):166-73. [Medline].

  9. Auber F, Lortat-Jacob S, Sarnacki S, et al. Surgical management and genotype/phenotype correlations in WT1 gene-related diseases (Drash, Frasier syndromes). J Pediatr Surg. 2003 Jan. 38(1):124-9; discussion 124-9. [Medline].

  10. Call KM, Glaser T, Ito CY, et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990 Feb 9. 60(3):509-20. [Medline].

  11. Coppes MJ, Campbell CE, Williams BR. The role of WT1 in Wilms tumorigenesis. FASEB J. 1993 Jul. 7(10):886-95. [Medline].

  12. Coppes MJ, Huff V, Pelletier J. Denys-Drash syndrome: relating a clinical disorder to genetic alterations in the tumor suppressor gene WT1. J Pediatr. 1993 Nov. 123(5):673-8. [Medline].

  13. Dumoucel S, Gauthier-Villars M, Stoppa-Lyonnet D, et al. Malformations, genetic abnormalities, and Wilms tumor. Pediatr Blood Cancer. 2014 Jan. 61(1):140-4. [Medline].

  14. Eddy AA, Mauer SM. Pseudohermaphroditism, glomerulopathy, and Wilms tumor (Drash syndrome): frequency in end-stage renal failure. J Pediatr. 1985 Apr. 106(4):584-7. [Medline].

  15. Gessler M, Konig A, Bruns GA. The genomic organization and expression of the WT1 gene. Genomics. 1992 Apr. 12(4):807-13. [Medline].

  16. Habib R. Nephrotic syndrome in the 1st year of life. Pediatr Nephrol. 1993 Aug. 7(4):347-53. [Medline].

  17. Habib R, Loirat C, Gubler MC, et al. The nephropathy associated with male pseudohermaphroditism and Wilms' tumor (Drash syndrome): a distinctive glomerular lesion--report of 10 cases. Clin Nephrol. 1985 Dec. 24(6):269-78. [Medline].

  18. Heathcott RW, Morison IM, Gubler MC, et al. A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X. Hum Mutat. 2002 Apr. 19(4):462. [Medline].

  19. Jadresic L, Leake J, Gordon I, et al. Clinicopathologic review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome). J Pediatr. 1990 Nov. 117(5):717-25. [Medline].

  20. Jensen JC, Ehrlich RM, Hanna MK, et al. A report of 4 patients with the Drash syndrome and a review of the literature. J Urol. 1989 May. 141(5):1174-6. [Medline].

  21. Kashtan CE. Glomerular disease. Semin Nephrol. 1999 Jul. 19(4):353-63. [Medline].

  22. Kessler O, Franco I, Jayabose S, et al. Is contralateral exploration of the kidney necessary in patients with Wilms tumor?. J Urol. 1996 Aug. 156(2 Pt 2):693-5. [Medline].

  23. Kist-van Holthe JE, Ho PL, Stablein D, Harmon WE, Baum MA. Outcome of renal transplantation for Wilms' tumor and Denys-Drash syndrome: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. 2005 Jun. 9(3):305-10. [Medline].

  24. Koziell A, Grundy R. Frasier and Denys-Drash syndromes: different disorders or part of a spectrum?. Arch Dis Child. 1999 Oct. 81(4):365-9. [Medline].

  25. Kucinskas L, Rudaitis S, Pundziene B, Just W. Denys-Drash syndrome. Medicina (Kaunas). 2005. 41(2):132-4. [Medline].

  26. Little M, Holmes G, Bickmore W, et al. DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations. Hum Mol Genet. 1995 Mar. 4(3):351-8. [Medline].

  27. Little S, Hanks S, King-Underwood L, et al. A WT1 exon 1 mutation in a child diagnosed with Denys-Drash syndrome. Pediatr Nephrol. 2005 Jan. 20(1):81-5. [Medline].

  28. Mesrobian HG. Wilms tumor: past, present, future. J Urol. 1988 Aug. 140(2):231-8. [Medline].

  29. Motoyama O, Arai K, Kawamura T, et al. Clinical course of congenital nephrotic syndrome and Denys-Drash syndrome in Japan. Pediatr Int. 2005 Dec. 47(6):607-11. [Medline].

  30. Mueller RF. The Denys-Drash syndrome. J Med Genet. 1994 Jun. 31(6):471-7. [Medline].

  31. Pritchard-Jones K. The Wilms tumour gene, WT1, in normal and abnormal nephrogenesis. Pediatr Nephrol. 1999 Sep. 13(7):620-5. [Medline].

  32. Rauscher FJ. The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J. 1993 Jul. 7(10):896-903. [Medline].

  33. Royer-Pokora B, Beier M, Henzler M, et al. Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. Am J Med Genet A. 2004 Jun 15. 127(3):249-57. [Medline].

  34. Rudin C, Pritchard J, Fernando ON, Duffy PG, Trompeter RS. Renal transplantation in the management of bilateral Wilms' tumour (BWT) and of Denys-Drash syndrome (DDS). Nephrol Dial Transplant. 1998 Jun. 13(6):1506-10. [Medline].

  35. Sanpakit K, Triwatanawong J, Sumboonnanonda A. Long-term outcome in pediatric renal tumor survivors: experience of a single center. J Pediatr Hematol Oncol. 2013 Nov. 35(8):610-3. [Medline].

  36. Schumacher V, Scharer K, Wuhl E, et al. Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int. 1998 Jun. 53(6):1594-600. [Medline].

  37. Schumacher V, Schneider S, Figge A, et al. Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. Proc Natl Acad Sci U S A. 1997 Apr 15. 94(8):3972-7. [Medline].

  38. Schumacher V, Thumfart J, Drechsler M, et al. A novel WT1 missense mutation presenting with Denys-Drash syndrome and cortical atrophy. Nephrol Dial Transplant. 2006 Feb. 21(2):518-21. [Medline].

  39. Swiatecka-Urban A, Mokrzycki MH, Kaskel F, et al. Novel WT1 mutation (C388Y) in a female child with Denys-Drash syndrome. Pediatr Nephrol. 2001 Aug. 16(8):627-30. [Medline].

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