Wilms Tumor, Aniridia, Genitourinary Anomalies, And Mental Retardation Syndrome

A number sign (#) is used with this entry because the WAGR syndrome is a contiguous gene syndrome due to deletion, either microscopic or submicroscopic, at chromosome 11p13 in a region containing the WT1 (607102) and PAX6 (607108) genes.

A subphenotype of WAGR including obesity (WAGRO) has been associated with haploinsufficiency for the BDNF gene (113505) and is discussed in 612469.

Clinical Features

Miller et al. (1964) first described the association of aniridia, hemihypertrophy, and other congenital anomalies with Wilms tumor. The syndrome subsequently became known as the WAGR syndrome. In addition to 'genitourinary abnormalities,' the 'G' in WAGR syndrome may refer to 'ambiguous genitalia' (Riccardi et al., 1978) or 'gonadoblastoma' (Anderson et al., 1978).

Riccardi et al. (1978) observed a triad of aniridia, ambiguous genitalia, and mental retardation (AGR triad) in 3 patients with an interstitial deletion of the short arm of chromosome 11. One patient also had Wilms tumor.

Among 6 cases of aniridia, Francke et al. (1978) showed that Wilms tumor was not present in all cases: monozygotic twins had aniridia and mental retardation, but only 1 had Wilms tumor, and only 1 of the other 4 patients had Wilms tumor. The deleted segment common to all was the distal half of 11p13.

Anderson et al. (1978) described aniridia, cataract, and gonadoblastoma in a mentally retarded girl with an interstitial deletion of the short arm of chromosome 11. Gonadoblastoma occurs as part of the WAGR complex (Junien et al., 1980; Turleau et al., 1981).

In a report that focused on the aniridia component of the WAGR syndrome, Gilgenkrantz et al. (1982) analyzed the reported cases of aniridia with interstitial del(11)p. They reported a unique observation of hypertrophic cardiomyopathy in association with aniridia and catalase (CAT; 115500) deficiency in a patient with del(11)(p15.1p12). Riccardi et al. (1982) reported a patient with Wilms tumor and iris dysplasia, not aniridia. In the UK, Shannon et al. (1982) found the incidence of aniridia in cases of Wilms tumor to be 1 in 43. A survey detected 8 living and 3 dead children with Wilms tumor and aniridia. All 8 living children had deletion of 11p13. A high incidence of bilateral Wilms tumor (36%), male sex, early presentation, and advanced maternal age were features of the combined cases. Among 49 children with Wilms tumor without aniridia, only 1 had bilateral renal tumors.

Using high resolution chromosome banding, Marshall et al. (1982) studied 14 patients with aniridia. Seven were familial and had normal chromosomes; of 7 sporadic cases, 1 showed normal chromosomes and 6 had interstitial deletion of 11p of various lengths. Band 11p13 was included in the deletion in all 6 cases.

Little et al. (1993) suggested that the severe nephropathy associated with Denys-Drash syndrome (194080), which frequently leads to early renal failure, may result from the action of altered WT1 in blocking the normal activity of the wildtype protein. In contrast, because of the less severe genital anomalies and apparent lack of nephropathy associated with WAGR, a reduced WT1 dosage during embryogenesis is thought to have a less pronounced effect on development, especially on that of the renal system.

Breslow et al. (2000) reviewed nearly 6,000 patients enrolled in 4 clinical trials of the U. S. National Wilms Tumor Study Group between 1969 and 1995 who were followed until death or for a median of 11.0 years of survival for the onset of renal failure. Of 22 patients with Denys-Drash syndrome, 13 developed renal failure; of 46 patients with WAGR, 10 developed renal failure. The cumulative risks of renal failure at 20 years were 62% and 38%, respectively. The findings suggested that nephropathy is not associated uniquely with missense mutations in the WT1 gene and that patients with Wilms tumor and aniridia or genitourinary abnormalities should be followed closely throughout life for signs of nephropathy.

WAGR Syndrome with Atypical Eye Findings

Kawase et al. (2001) reported a case of WAGR syndrome with atypical eye findings. The boy presented at 1 month of age with microphthalmos bilaterally, microcornea and corneal cyst in the right eye, and corneal opacity (consistent with Peters anomaly) and absent anterior chamber in the left eye. Electroretinogram was normal in the right eye and subnormal in the left eye, suggesting retinal dysfunction. The child was found to have bilateral Wilms tumors at age 3 years. He also had undescended testes and mental retardation. Chromosome analysis revealed deletion of chromosome 11p15.1-p13.

Cytogenetics

Puissant et al. (1988) reported a patient with WAGR and a de novo reciprocal translocation 46,XY,t(5;11)(q11;p13). On Southern blot analysis, the gene encoding catalase had been deleted, but the gene encoding the beta subunit of follicle-stimulating hormone (FSHB) was intact. Evidence from studies of balanced translocations and other observations had suggested that the genitourinary dysplasia, like aniridia, was due to a separate gene in close proximity to the WT1 gene in band 11p13 (Bickmore et al., 1989; Glaser et al., 1989). By HRAS1-selected chromosome transfer, Porteous et al. (1987) defined 10 distinct regions of the short arm of chromosome 11, 5 of which subdivided band 11p13. They also mapped 2 independent 11p13 translocation breakpoints to within the smallest region of overlap defined by the WAGR deletions. One came from a patient with familial aniridia and the second from a patient with Potter facies and genitourinary dysplasia (urethral and ureteral atresia and bilateral cryptorchidism). Porteous et al. (1987) raised the question of whether Wilms tumor and genitourinary dysplasia are alternative manifestations of mutations at the same locus. A separate gene coding for genitourinary dysplasia (symbolized GUD) was also suggested by Bonetta et al. (1989), who found that the deletion breakpoint of a translocation t(11;2)(p13;p11) in a patient with Potter facies and genitourinary dysplasia mapped to the same 225-kb pulsed field gel electrophoresis fragment as did the fragment deleted in Wilms tumor. However, van Heyningen et al. (1990) suggested that the Wilms tumor gene itself may be responsible for abnormalities of genitourinary development in WAGR as a pleiotropic effect. The suggestion was based on the observations that the tumor predisposition and the genitourinary malformations map to precisely the same area and that the WT candidate gene shows expression in both the developing kidney and gonads. That there is no GUD gene separate from the WT1 gene is supported by the fact that the Denys-Drash syndrome (nephropathy, Wilms tumor, and genital anomalies; 194080) is caused by specific point mutations in the WT1 gene (e.g., 607102.0003).

Diagnosis

Apparent close linkage of the region determining the WAGR syndrome to the catalase locus (CAT; 115500) means that assay of catalase activity could usefully indicate those cases of new-mutation aniridia that should have surveillance for the development of renal or gonadal tumors (Junien et al., 1980).

Molecular Genetics

In WAGR syndrome, aniridia is due to the PAX6 gene, whereas the other features are probably due to the WT1 gene.

Animal Model

AGR syndrome is a subgroup of WAGR syndrome in which patients do not develop Wilms tumor and is associated with deletion of chromosome 11p14.1-p13, where the LGR4 gene (GPR48; 606666) is located. Yi et al. (2014) found that mice lacking Lgr4 had aniridia, polycystic kidney disease, genitourinary abnormalities, and mental retardation, similar to the pathologic defects of AGR syndrome. Inactivation of Lgr4 significantly increased apoptosis and decreased expression of multiple genes involved in development of WAGR syndrome-related organs. Yi et al. (2014) proposed that LGR4 is a candidate gene for the pathogenesis of AGR syndrome.