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รltima actualizaciรณn: April 13, 2016
Aรฑos publicados: 1993, 2000, 2010, 2013, 2016
NORD gratefully acknowledges Agnieszka Swiatecka-Urban, MD, FASN, Assistant Professor of Pediatrics and Cell Biology, Childrenโs 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 a genetic 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.
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, is 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
TTY: (866) 411-1010
Email: [email protected]
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
Childrenโs Hospital of Pittsburgh
University of Pittsburgh School of Medicine
Email: [email protected]
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.
Childrenโs Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Bethesda, MD: Childrenโs Oncology Group; Mar 2006.
Kist-van Holthe JE, Ho PL, Stablein D, Harmon WE, Baum MA. Outcome of renal transplantation for Wilmsโ 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; Medscape. March 27, 2014. https://emedicine.medscape.com/article/943103-overview Accessed April 13, 2016.
McKusick VA., Ed. Online Mendelian Inheritance in Man (OMIM); https://omim.org/entry/194080?search=194080&highlight=194080 Last Update:11/18/10. Accessed April 13, 2016.
Niaudet P. Denys-Drash Syndrome; Orphanet; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=220&lng=EN Last Update: 2/07. Accessed April 13, 2016.
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Aprende mรกs https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View report