Denys-Drash Syndrome

Denys-Drash Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Denys-Drash Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • DDS
  • Drash syndrome
  • Wilms tumor, pseudo or true hermaphroditism
  • nephropathy and disorders of sexual development

Disorder Subdivisions

  • None

General Discussion

Denys-Drash syndrome (DDS) is characterized by abnormal kidney function (congenital nephropathy), a cancerous tumor of the kidney called Wilms tumor, and disorders of sexual development in affected males. Most affected females have normal genitalia. DDS is agenetic disorder caused by mutations in the Wilms tumor suppressor gene, WT1.

Symptoms

The initial symptoms of DDS may be similar to nephrotic syndrome and include edema, abdominal distention and recurrent infections, sometimes present at birth but more often developing between 1 and 2 years of age. Many affected children develop high blood pressure (hypertension). The kidney abnormality that results in abnormal kidney function is termed diffuse mesangial sclerosis and usually results in a progression to renal failure during the first three years of life.



Wilms tumor occurs in approximately 90% of affected individuals and is sometimes the first clinical sign of the disease. Signs of Wilms tumor can include abdominal swelling, blood in the urine, decreased urination, low-grade fever, loss of appetite, paleness, weight loss and lethargy.



Disorders of sexual development also occur in males with DDS and are rare in females with this condition. These are conditions in which a boy has normal male chromosomes (46, XY), but the external genitals are incompletely formed, ambiguous, or clearly female. Testes may be normal, malformed, absent, or internal (undescended). Affected individuals of both genders are at risk for cancers of the testes or ovaries.

Causes

DDS is a genetic disorder caused by mutations in the Wilms tumor suppressor gene, WT1. The vast majority of the mutations occur in one of two areas of the gene located on chromosome 11, called exon 8 or exon 9. While mutations in a single copy of the WT1 gene are sufficient to produce nephropathy and disorders of sexual development, Wilms tumor results from mutations in both copies of the WT1 gene. The abnormal product of a single copy of mutant WT1 gene interferes with the function of the unaffected copy of the WT1 gene and changes its normal regulatory function. This is sufficient to produce nephropathy and disorders of sexual development. In contrast, Wilms tumor is a result of two independent events (two-hit hypothesis) that sequentially lead to loss of function of both copies of the WT1 gene. The first mutation in a single copy of the WT1 gene (first hit) leads to persistence of an undifferentiated tissue in the developing kidney, called mesenchyme. Subsequently, another mutation (second hit) in the second copy causes uncontrolled cell growth in the kidney and Wilms tumor formation.



Most cases of DDS are not inherited from a parent and occur as the result of a new gene mutation.

Affected Populations

The prevalence of DDS is not known. Over 200 cases have been reported in the medical literature.

Standard Therapies

Diagnosis

DDS is diagnosed by physical signs and symptoms, laboratory tests, imaging studies, and kidney biopsy to document diffuse mesangial sclerosis. Molecular genetic testing for the WT1 gene is available to confirm the diagnosis.



Treatment

The treatment of DDS is supportive and requires consultation with a pediatric nephrologist, pediatric oncologist, pediatric surgeon, pediatric endocrinologist and geneticist.



Medical care involves management of fluids and electrolytes, treatment for hypertension and chemotherapy for Wilms tumor, if present. Prophylactic removal of kidneys (nephrectomy) is recommended when the diagnosis of DDS is made prior to development of Wilms tumor. Renal replacement therapy, including dialysis and/or kidney transplantation, are recommended following end-stage renal failure or nephrectomy. Surgical removal of internal reproductive organs (gonadectomy) is recommended because of the high risk for gonadal malignancy.



Genetic counseling is recommended. Other treatment is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



For information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/



Contact for additional information about Denys-Drash syndrome:



Agnieszka Swiatecka-Urban, M.D., F.A.S.N.

Assistant Professor of Pediatrics and Cell Biology and Physiology

Children's Hospital of Pittsburgh,

University of Pittsburgh School of Medicine

Email: asurban@pitt.edu

References

JOURNAL ARTICLES

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



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



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



Children's Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Bethesda, MD: Children's Oncology Group; Mar 2006.



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. Jun 2005;9(3):305-10.



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



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. Nov 2005;174(5):1972-5.



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



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



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



INTERNET

Swiatecka-Urban, A and Devarajan P. Denys-Drash Syndrome; eMedicine. March 13, 2012. http://emedicine.medscape.com/article/943103-overview Accessed:February 21, 2013.



McKusick VA., Ed. Online Mendelian Inheritance in Man (OMIM); http://omim.org/entry/194080 Last Update:11/18/10. Accessed:February 21, 2013.



Niaudet P. Denys-Drash Syndrome; Orphanet; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=220&lng=EN Last Update: 2/07. Accessed:February 21, 2013.

Resources

American Kidney Fund, Inc.

11921 Rockville Pike

Suite 300

Rockville, MD 20852

USA

Tel: (800)638-8299

Email: helpline@kidneyfund.org

Internet: http://www.kidneyfund.org



American Childhood Cancer Organization

10920 Connecticut Ave

Suite A

Kensington, MD 20895

Tel: (301)962-3520

Fax: (301)962-3521

Tel: (800)366-2223

Email: staff@acco.org

Internet: http://www.candlelighters.org



National Kidney Foundation

30 East 33rd Street

New York, NY 10016

Tel: (212)889-2210

Fax: (212)689-9261

Tel: (800)622-9010

Email: info@kidney.org

Internet: http://www.kidney.org



American Cancer Society, Inc.

250 Williams NW St

Ste 6000

Atlanta, GA 30303

USA

Tel: (404)320-3333

Tel: (800)227-2345

TDD: (866)228-4327

Internet: http://www.cancer.org



Rare Cancer Alliance

1649 North Pacana Way

Green Valley, AZ 85614

USA

Internet: http://www.rare-cancer.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Friends of Cancer Research

1800 M Street NW

Suite 1050 South

Washington, DC 22202

Tel: (202)944-6700

Email: info@focr.org

Internet: http://www.focr.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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