WT1-Associated Syndromes – Definition

Three phenotypes are involved: WAGR syndrome (WAGR, OMIM#194072), Denys-Drash syndrome (DDS, OMIM #194080), and Frasier syndrome (FS, OMIM #136680). These syndromes occur in people with different genetic defects of the WT1 gene and are associated with an increased risk of Wilms tumors and other abnormalities.

Synonym:

Gene:

WT1

Gen­e product:

WT1

Function:

WT1 encodes for a zinc finger protein with multiple isoforms. The gene product is a transcription factor that regulates cell growth and the differentiation of the kidneys, gonads, spleen, and mesothelium.

Pattern of inheritance:

Autosomal dominant

Prevalence:

Rare

Genotype-phenotype correlation:

The mutation type determines whether WAGR, DDS, or FS is present. The greatest risk of nephroblastoma is linked to truncating mutations in the exon 8/9 hotspot. Patients with truncating mutations have a higher risk of bilateral nephroblastomas than patients with missense mutations.

  • WAGR: microdeletion 11p13 (WT1 and PAX6)
  • DDS: heterozygous point mutations in the DNA-binding domain of WT1 (exons 8 and 9)
  • FS: heterozygous mutations of the splice donor site of intron 9 of WT1

Penetrance:

Unknown

Overview of the Chapters on This Page:

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients
  • Further Information (e.g., Links to Support Groups)

  • Clinical Presentation

  • Special Features of Treatment

  • Recommendations for Early Detection in Your Patients
  • Further Information (e.g., Links to Support Groups)

WT1-Associated Syndromes – Diagnosis

Diagnosis

The diagnosis is made clinically and can be verified by means of mutation analysis.

Differential Diagnoses

Clinical Presentation

WAGR

Wilms tumor, aniridia, urogenital malformation, mental retardation; Wilms tumor risk 30-60%

DDS

Diffuse mesangial sclerotization, early kidney failure, genital malformations, gonadal dysgenesis; Wilms tumor risk 74-90%

FS

Focal segmental glomerulosclerosis, gonadal dysgenesis, genital malformations; Wilms tumor risk not greatly increased

Basically

WT1-associated gonadoblastomas may occur when sexual development is disrupted in individuals with FS or DDS who have a 46,XY karyotype. In these patients, the development of gonadoblastomas appears to be closely linked to the presence of gonadal dysgenesis, and it appears to occur with FS and DDS at approximately the same frequency (in over 40% of patients). Even though most gonadoblastomas develop in adolescents and young adults, these tumors have also been diagnosed in toddlers. The gonadoblastoma risk is low in individuals with matching karyotype and gender.

Special Features of Treatment

Individuals suffering from WT1-associated syndromes should be cared for by a multi-professional team of experienced nephrologists, pediatric oncologists, etc.

The treatment of a patient with a Wilms tumor with WAGR, DDS, or FS should be discussed with the principal investigator of the nephroblastoma study.

All individuals with FS or DDS and a 46,XY karyotype should be checked for gonadal dysgenesis. If a gonadal dysgenesis is confirmed, a gonadectomy is recommended. About the specific approach, we refer to the following recommendations:

Diagnosis of WT1-Associated Syndromes- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Diagnosis of WT1-Associated Syndromes- What's Next?

Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.

Recommendations for Early Detection in Your Patients

Ultrasound of the kidneys every 3 months until the age of 7

WT1-Associated Syndromes – Further Information

Additional Resources

Unfortunately, we are currently not aware of any support groups for patients with WT1-Associated syndrome. New information will be added as soon as it becomes available.