Screening Children Predisposed to Wilms Tumor
Children with a significantly increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome, WAGR syndrome, Denys-Drash syndrome, idiopathic hemihypertrophy, or sporadic aniridia) should be screened with ultrasound every 3 months at least until they reach age 8 years.[13,14,15,30]
Approximately 10% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with either Wilms tumor or hepatoblastoma being the most common, although adrenal tumors can also occur. Children with hemihypertrophy are also at risk for developing liver and adrenal tumors. Screening with abdominal ultrasound and serum alpha-fetoprotein is suggested until age 4 years; after age 4, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require the child to fast for the exam.
Children with Klippel-Trénaunay syndrome, a unilateral limb overgrowth syndrome, had been considered to be at increased risk for developing Wilms tumor. The risk of Wilms tumor in children with Klippel-Trénaunay syndrome, when assessed using the National Wilms Tumor Study (NWTS) database, was no different than in the general population and routine ultrasound surveillance is not recommended.
Genetics of Wilms Tumor
Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes. Several, but not all, will be discussed here.
Wilms tumor 1gene (WT1)
The WT1 gene is located on the short arm of chromosome 11 (11p13). The normal function of WT1 is required for normal genitourinary development and is important for differentiation of the renal blastema. Germline mutations in WT1 have been found in about 2% of phenotypically normal children with Wilms tumor. Germline WT1 mutations in children with Wilms tumor does not confer a poor prognosis per se. The offspring of those with germline mutation in WT1 may also be at increased risk of developing Wilms tumor. Because deletion of WT1 was the first mutation found to be associated with Wilms tumor, WT1 was assumed to be a conventional tumor suppressor gene. However, non-inactivating mutations can result in altered WT1 protein function that also results in Wilms tumor, such as in the Denys-Drash syndrome.
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).