WT1 mutation is more common in those children with Wilms tumor and one of the following:
- WAGR syndrome, Denys-Drash syndrome, or sporadic aniridia.
- Genitourinary anomalies, including hypospadias and cryptorchidism.
- Bilateral Wilms tumor.
- Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
- Stromal and rhabdomyomatous differentiation.
WT1mutation, aniridia, and genitourinary malformation
The observation that lead to the discovery of WT1 was that children with WAGR syndrome (aniridia, genitourinary anomalies, and mental retardation) were at high risk (>30%) for developing Wilms tumor. Germline mutations were then identified at chromosome 11p13 in children with WAGR syndrome. Deletions involved a set of contiguous genes that included WT1 and the PAX6 gene (responsible for aniridia). Aniridia is characterized by hypoplasia of the iris and it occurs in sporadic or familial cases and has an autosomal dominant inheritance. Mutations in the PAX6 gene lead to aniridia. The PAX6 gene is located on chromosome 13 closely associated with the WT1 gene, deletion of which confers the increased risk of Wilms tumor. Some of the sporadic cases of aniridia are caused by large chromosomal deletions that also include the Wilms tumor gene – WT1. This results in an increased relative risk of 67-fold (95% confidence interval [CI], 8.1–241) of developing Wilms tumor in children with sporadic aniridia. Patients with sporadic aniridia and a normal WT1 gene, however, are not at increased risk for developing Wilms tumor. Children with familial aniridia generally have a normal WT1 gene and are not at an increased risk of Wilms tumor. The mental retardation in WAGR syndrome may be secondary to deletion of other genes including SLC1A2 or BDNF (brain-derived neurotrophic factor).
The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%. Patients with sporadic aniridia should be screened with ultrasound every 3 months until they reach age 8 years, unless genetic testing confirms that they are negative for WT1.[15,30]
Monitoring for late renal failure
Children with WAGR syndrome or other germline WT1 mutations are at increased risk of eventually developing hypertension, nephropathy, and renal failure and should be monitored throughout their lives. Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lesser risk but should be monitored for nephropathy or renal failure. Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and should be monitored. Features associated with germline WT1 mutations that increase the risk for developing renal failure are stromal predominant histology, bilaterality, intralobular nephrogenic rests, and Wilms tumor diagnosed before age 2 years.