Table 1. Syndromes and Conditions Associated With Wilms Tumor continued...
WT1deletion and WAGR syndrome
The observation that led to the discovery of WT1 was that children with WAGR syndrome (Wilms tumor, 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.
Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Some of the sporadic cases of aniridia are caused by large chromosomal deletions that also include WT1. This results in a 67-fold increased relative risk (95% confidence interval [CI], 8.1-241) of developing Wilms tumor in children with sporadic aniridia. The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%. Seventy-seven percent of aniridia patients with submicroscopic WT1 deletions detectable by high-resolution fluorescence in situ hybridization (FISH) analysis presented with Wilms tumor compared with 42.5% of aniridia patients with visible deletions detected by microscopy. Patients with sporadic aniridia and a normal WT1 gene, however, are not at increased risk of developing Wilms tumor. Children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[15,46]
Children with WAGR syndrome or other germline WT1 mutations are at increased risk of developing hypertension, nephropathy, and renal failure and are monitored throughout their lives. Patients with Wilms tumor and aniridia without genitourinary abnormalities are at less risk but are monitored for nephropathy or renal failure. Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and are monitored. Features associated with germline WT1 mutations that increase the risk of developing renal failure include the following:
- Stromal predominant histology.
- Bilateral disease.
- Intralobar nephrogenic rests.
- Wilms tumor diagnosed before age 2 years.
Age at tumor diagnosis, frequency of bilaterality, and risk of late-onset renal compromise may vary with the type of mutation.