Three groups of congenital malformations are associated with an increased risk for Wilms tumor. These are WAGR syndrome (i.e., Wilms tumor, aniridia, genital abnormalities, and mental retardation); Denys-Drash syndrome (DDS), and Beckwith-Wiedemann syndrome (BWS). Of patients with WAGR syndrome approximately one in three will go on to develop this tumor. Another group of patients, those with so-called “Denys-Drash syndrome” (DDS), have an even higher risk (approximately 90%) of Wilms tumor. Patients with the WAGR syndrome, as the name indicates, have Wilms tumor, aniridia, genital abnormalities and mental retardation. DD syndrome is characterized by gonadal dysgenesis and early onset nephropathy leading to renal failure. Both of these conditions are associated with abnormalities of the Wilms tumor 1 (WT1) gene, located on 11p13. The nature of the genetic aberration differs, however: Patients with WAGR syndrome demonstrate loss of genetic material (i.e., deletions) of WT1, while persons with DDS harbor a dominant negative inactivating mutation in WT1 that interferes with the function of normal WT1 protein made from the other WT1 allele. WT1 is critical to normal renal and gonadal development; it is not surprising, therefore, that constitutional inactivation of one copy of this gene results in genitourinary abnormalities in humans.
A third group of patients, those with Beckwith-Wiedemann syndrome (BWS), also are at increased risk for the development of Wilms tumor. These patients exhibit enlargement of individual body organs (e.g., tongue, kidneys, or liver) or entire body segments (hemihypertrophy); enlargement of adrenal cortical cells (adrenal cytomegaly) is a characteristic microscopic feature. BWS is an example of a disorder of genomic imprinting (see earlier). The genetic locus that is involved in these patients is in band p15.5 of chromosome 11 distal to the WT1 locus. Although this locus is called “WT2” for the second Wilms tumor locus, the gene involved has not been identified. This region contains at least 10 genes that normally are expressed from only one of the two parental alleles, with transcriptional silencing of the other parental homologue by methylation of the promoter region located upstream of the transcription start site. Of all candidate “WT2” genes, imprinting abnormalities of insulinlike growth factor-2 (IGF2) have the strongest relationship to tumor predisposition in persons with BWS. IGF2 normally is expressed solely from the paternal allele, whereas the maternal allele is imprinted. In some Wilms tumors, loss of imprinting (i.e., reexpression of IGF2 by the maternal allele) can be demonstrated, leading to overexpression of the IGF2 protein, which is postulated to result in both organ enlargement and tumorigenesis. Thus, these associations suggest that in some cases, congenital malformations and tumors represent related manifestations of genetic lesions affecting a single gene or closely linked genes. In addition to Wilms tumors, patients with BWS also are at increased risk for the development of hepatoblastoma, adrenocortical tumors, rhabdomyosarcomas, and pancreatic tumors.
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Fig. 7.35 Retinoblastoma.(A)Poorlycohesivetumorinretinaisseenabuttingtheopticnerve.(B)Higher-powerviewshowingFlexner-Wintersteinerrosettes(arrow) andnumerousmitoticfigures.