Wilms Tumor, Nephroblastoma - WT1

Clinical Features

Wilms tumor (nephroblastoma) is the most common malignancy of the kidney in children and the young. Wilms tumor development origins from nephrogenic rests, which are present in approximately 1% of all newborns but normally regress in early childhood. The persistence of these cells, which then predispose to an increased risk of developing Wilms tumor, seems to be dependent on genetic mutations.

The vast majority of children with Wilms tumor predisposition syndromes have nephrogenic rests. Intralobar nephrogenic rests, which are usually solitary are associated with two syndromes associated with WT1 mutations: WAGR (Wilms tumor-aniridia-genital anomalies-retardation) and Denys-Drash syndrome. Perilobar rests, which are often multiple, are associated with Beckwith-Wiedemann syndrome.

Symptoms:

leading symptome is a painless tumor growth in the abdomen / increase in abdominal girth
abdominal pain and fever
anemia
obstipation
hematuria
hypertension

Attendant Symptoms of Wilms tumor:

aniridia
visceromegalie
hemihypertrophy and urogenital malformations
naevi
horseshoe kidney
cryptorchism

Genetic Information

To date, only one Wilms tumor gene, WT1, has been identified. The syndromes in which germline WT1 mutations occur are:

WAGR syndrome, caused by deletions of chromosome 11p13 that include both PAX6 and WT1

Denys-Drash syndrome (males with undermasculinized external genitalia that can range from ambiguous to normal appearing female, diffuse mesangial sclerosis, and Wilms tumor) caused by missense mutations in WT1, almost invariably in exons 8 and 9

Frasier syndrome (males with undermasculinized external genitalia that can range from ambiguous to normal appearing female, focal segmental glomerulosclerosis, gonadoblastoma) caused by point mutations in the WT1 intron 9 donor splice site

Beckwith-Wiedemann syndrome (BWS), which is characterized by macroglossy, exomphalos, gigantism and visceromegalie. BWS is also associated with an increased risk of developing certain tumors: hepatoblastoma, rhabdomyosarcoma, caner of the adrenal gland and Wilms tumor. The BWS is caused by deletions, duplications, insertions and epimutations in the the chromosomal region 11q15.5 (H19 DMR), where the so far unidentified WT2-gene is assumed.

The gene WT1 consists of 10 exons and is coding for a zinc-finger DNA-binding protein with a length of 429 aminoacids. The WT1-Protein is either a transcription activator or a repressor, dependend on the cellular and / or chromosomal context.

Prevalence

Wilms tumor has the potential for both local and distant spread and is responsible for 6-8% of all malignant tumors of the childhood. The incidence is approximately 1:10.000 and peaks between 1 and 4 years of age. In adults the nephroblastoma is a very rare disease.