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Denys-Drash syndrome

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Description

Denys-Drash syndrome is a condition that affects the kidneys and genitalia.

Denys-Drash syndrome is characterized by kidney disease that begins within the first few months of life. Affected individuals have a condition called diffuse glomerulosclerosis, in which scar tissue forms throughout glomeruli, which are the tiny blood vessels in the kidneys that filter waste from blood. In people with Denys-Drash syndrome, this condition often leads to kidney failure in childhood. People with Denys-Drash syndrome have an estimated 90 percent chance of developing a rare form of kidney cancer known as Wilms tumor. Affected individuals may develop multiple tumors in one or both kidneys.

Although males with Denys-Drash syndrome have the typical male chromosome pattern (46,XY), they have gonadal dysgenesis, in which external genitalia do not look clearly male or clearly female (ambiguous genitalia) or the genitalia appear completely female. The testes of affected males are undescended, which means they are abnormally located in the pelvis, abdomen, or groin. As a result, males with Denys-Drash are typically unable to have biological children (infertile).

Affected females usually have normal genitalia and have only the kidney features of the condition. Because they do not have all the features of the condition, females are usually given the diagnosis of isolated nephrotic syndrome.

Frequency

The prevalence of Denys-Drash syndrome is unknown; at least 150 affected individuals have been reported in the scientific literature.

Causes

Mutations in the WT1 gene cause Denys-Drash syndrome. The WT1 gene provides instructions for making a protein that regulates the activity of other genes by attaching (binding) to specific regions of DNA. On the basis of this action, the WT1 protein is called a transcription factor. The WT1 protein plays a role in the development of the kidneys and gonads (ovaries in females and testes in males) before birth.

WT1 gene mutations that cause Denys-Drash syndrome lead to the production of an abnormal protein that cannot bind to DNA. As a result, the activity of certain genes is unregulated, which impairs the development of the kidneys and reproductive organs. Abnormal development of these organs leads to diffuse glomerulosclerosis and gonadal dysgenesis, which are characteristic of Denys-Drash syndrome. Abnormal gene activity caused by the loss of normal WT1 protein increases the risk of developing Wilms tumor in affected individuals.

Denys-Drash syndrome has features similar to another condition called Frasier syndrome, which is also caused by mutations in the WT1 gene. Because these two conditions share a genetic cause and have overlapping features, some researchers have suggested that they are part of a spectrum and not two distinct conditions.

Inheritance

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Other Names for This Condition

  • DDS
  • Drash syndrome
  • nephropathy, Wilms tumor, and genital anomalies
  • Wilms tumor and pseudohermaphroditism

Additional Information & Resources

Genetic Testing Information

Genetic and Rare Diseases Information Center

Research Studies from ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Andrade JG, Guaragna MS, Soardi FC, Guerra-Júnior G, Mello MP, Maciel-Guerra AT. Clinical and genetic findings of five patients with WT1-related disorders. Arq Bras Endocrinol Metabol. 2008 Nov;52(8):1236-43. Citation on PubMed
  • Dai YL, Fu JF, Hong F, Xu S, Shen Z. WT1 mutation as a cause of 46 XY DSD and Wilm's tumour: a case report and literature review. Acta Paediatr. 2011 Jul;100(7):e39-42. doi: 10.1111/j.1651-2227.2011.02167.x. Epub 2011 Feb 14. Review. Citation on PubMed
  • Guaragna MS, Soardi FC, Assumpção JG, Zambaldi Lde J, Cardinalli IA, Yunes JA, de Mello MP, Brandalise SR, Aguiar Sdos S. The novel WT1 gene mutation p.H377N associated to Denys-Drash syndrome. J Pediatr Hematol Oncol. 2010 Aug;32(6):486-8. doi: 10.1097/MPH.0b013e3181e5e20d. Citation on PubMed
  • Niaudet P, Gubler MC. WT1 and glomerular diseases. Pediatr Nephrol. 2006 Nov;21(11):1653-60. Epub 2006 Aug 23. Review. Citation on PubMed
  • Yue Z, Pei Y, Sun L, Huang W, Huang H, Hu B, Yang J, Jiang X, Mo Y, Chen S, Lai KN, Wang Y. Clinical pictures and novel mutations of WT1-associated Denys-Drash syndrome in two Chinese children. Ren Fail. 2011;33(9):910-4. doi: 10.3109/0886022X.2011.605528. Epub 2011 Aug 18. Citation on PubMed
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