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NORD is very grateful to Agnieszka Swiatecka-Urban, MD, FASN, Assistant Professor of Pediatrics and Cell Biology and Physiology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, for assistance in the preparation of this report.
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.
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.
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.
The prevalence of DDS is not known. Over 200 cases have been reported in the medical literature.
Signs of the following disorders can be similar to those of Denys-Drash syndrome. Comparisons may be useful for a differential diagnosis.
Wilms tumor is the most common form of abdominal malignancy in children and accounts for 6 to 8 percent of all childhood cancers. Typically, this disease first appears by 3-4 years of age, but has also been diagnosed in adulthood. Wilms tumor can often be treated successfully, depending on the stage of the tumor at detection and the age and general health of the child. (For more information on this disorder, choose "Wilms tumor" as your search term in the Rare Disease Database.)
WAGR syndrome is a rare genetic syndrome in which there is a predisposition to several conditions, including certain malignancies, distinctive eye abnormalities, and/or mental retardation. "WAGR" is an acronym for the characteristic abnormalities associated with the syndrome. The acronym stands for (W)ilms' Tumor; (A)niridia, partial or complete absence of the colored region of the eye(s) (iris or irides); (G) Genitourinary abnormalities, such as undescended testicles or hypospadias in males, or internal genital or urinary anomalies in females; and Mental (R)etardation. A combination of two or more of these conditions is usually present in most individuals with WAGR syndrome. Affected individuals have a deletion of the WT1 gene. (For more information on this disorder, choose "WAGR" as your search term in the Rare Disease Database.)
Frasier syndrome is characterized by congenital nephropathy, female genitalia in individuals with normal male chromosomes (46, XY) and underdeveloped gonads (streak gonads) that may become cancerous. Nephropathy leads to end-stage renal disease late in childhood. Frasier syndrome is caused by mutations in the WT1 gene.
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.
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.
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
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For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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
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.
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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.
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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.
Report last updated: 2013/02/27 00:00:00 GMT+0