Denys-Drash syndrome

Other Names: Drash syndrome; Wilms tumor and pseudohermaphroditism; Nephropathy, wilms tumor, and genital anomalies; Pseudohermaphroditism, nephron disorder and Wilms' tumor; Nephropathy associated with male pseudohermaphroditism and Wilms' tumor

Denys-Drash syndrome is a condition that affects the kidneys and genitalia. Kidney disease typically begins in the first few months of life, often leading to kidney failure in childhood. In addition, up to 90 percent of people with this condition develop a rare form of kidney cancer known as Wilms tumor.

Epidemiology

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

Cause

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

Autosomal dominant pattern, a 50/50 chance.

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.

Signs and symptoms

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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Male pseudohermaphroditism
• Nephroblastoma
• Nephropathy
• Nephrotic syndrome
• Proteinuria(High urine protein levels)

30%-79% of people have these symptoms

• Hypertension

5%-29% of people have these symptoms

• Gonadal dysgenesis

Diagnosis

The diagnosis of a WT1 disorder is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in WT1 identified by molecular genetic testing.

Treatment

Glomerulopathy: Avoid immunosuppressants; consider renin-angiotensin-aldosterone system (RAAS) inhibition.

Disorder of testicular development: Management is often by a multidisciplinary team (medical geneticist, endocrinologist, urologist, and psychologist).

Treat Wilms tumor with standard oncology protocols an, when applicable, nephron-sparing surgery. Treat CAKUT as per standard care.

Prevent whenever possible gonadoblastoma by prophylactic gonadectomy.

Surveillance: Monitor for first appearance of the following: (1) proteinuria every six months until age ten years, yearly thereafter; (2) Wilms tumor every three months until age seven years. For ongoing issues with disorder of testicular development as per treating multidisciplinary team and for CAKUT as per treating nephrologist and/or urologist.

Agents/circumstances to avoid: Avoid treating glomerulopathy with immunosuppressants, as they are not effective and potentially toxic.

NIH genetic and rare disease info

• NIH info on Denys-Drash syndrome

Denys-Drash syndrome is a rare disease.

Denys-Drash syndrome Resources
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