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Home > Disclaimer > Wilms Tumor

The etiology of Wilms tumor remains unclear. The tumor may arise in 3 clinical settings:

1. Sporadic
2. Association with genetic syndromes
3. Familial/hereditary

 

Genetic Syndromes

• 5% of children with Wilms tumor have one of several syndromes. Syndrome manifestations vary and an affected child may not have all associated traits.

 

The WAGR syndrome

• Wilms tumor
• Aniridia (lack of an iris)
• Genitourinary malformations and mental retardation
• linked to a specific chromosome deletion.
  • The WAGR deletions encompass a number of contiguous genes including the aniridia gene PAX6 and the Wilms Tumor Suppressor gene WT1.
  • WT1 gene is important in normal kidney development.
  • WT1 is located within the short arm of one copy of chromosome 11p13.
  • The loss or mutation of one WT1 allele results in the genitourinary defects and constitutes the first event required for the development of Wilms tumor.
• Occurs only in male children.

Although mutation of WT1 is the initiating event in Wilms tumors arising in patients with WAGR, it is far more limited, but important in sporadic Wilms tumor.

Characteristics of genes associated with WAGR:

PAX6	Loss of an allele is responsible for aniridia This gene is responsible for the development of the brain, the eye, and nasal tissue
WT1	Wilms tumor suppressor gene Loss or mutation of one WT1 allele results in the genitourinary defects and constitutes the first event required for the development of Wilms’ tumor Mutations are far less common in sporadic Wilms’ tumor Very important gene in normal kidney development

 

Other associated genetic syndromes include Beckwith-Wiedmann, Denys-Drash and Perlman syndrome. They are summarized in the table below.

Table : Genetic Syndromes Associated with Wilms’ Tumors

Beckwith-Wiedeman Syndrome (BWS)	The major features of BWS include: Macroglossia Defects of closure of the abdominal wall Visceromegaly (liver, kidney, spleen) Muscular hypertrophy Advanced bone age Hemi-hypertrophy Malignant tumor development occurs in about 8% of children with BW and the most common of these is Wilms tumor.   Most BWS cases are sporadic, however, familial cases do occur with an autosomal dominant pattern of inheritance and showing variable penetrance and expressivity.   Linkage to chromosome 11p15.5 (WT2)
Denys-Drash Syndrome (DDS)	The major features include: Nephropathy (usually fatal unless there is a renal transplant) Dysgenetic male pseudohermaphroditism Wilms tumor
Perlman Syndrome (PS)	Has some features in common with BWS, but it is a distinct syndrome The major features include:   Characteristic facial appearance: Macrocephaly Small, short nose with depressed nasal bridge Deep-set eyes Low-set ears Macrosomia and organomegaly are common to PS and BWS, however, other features of BWS are not seen.   PS appears to show an autosomal recessive pattern of inheritance.   Increased risk for Wilms tumor

Additional genetic loci have been located at 16q, 1p and 7p. Patients who have loss of heterozygosity at 16q have a poor prognosis. P53 mutations are very rare in Wilms’ and may be associated with poor prognosis.

 

Hereditary or familial Wilms

• Defined as bilateral disease or a family history of Wilms.
• Relatively rare.
• Inheritance is usually dominant and occurs without other congenital abnormalities.
• Familial cases appear at an earlier age than unilateral disease.
• Genes implicated in familial Wilms include WT1, FWT1 and FWT2.

 

Additional factors:

• There is no convincing evidence that paternal occupation plays an etiological role1 .
• Previous epidemiological studies of Wilms tumor have suffered from a number of methodological limitations:
  • inadequate sample size
  • poor exposure assessment
  • low survey response rates
  • limited control of confounding factors
  • inability to evaluate potential etiologic heterogeneity of cases defined by biologic and other characteristics

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