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

A number sign (#) is used with this entry because of evidence that the WAGRO syndrome is a contiguous gene syndrome due to either microscopic or submicroscopic deletion in chromosome 11p13-p12 in a region containing the WT1 (607102), PAX6 (607108), and BDNF (113505) genes.

Description

For a detailed discussion of the WAGR syndrome, see 194072. In a subgroup of individuals with the WAGR syndrome, obesity develops. The phenotype in this subset is associated with haploinsufficiency for the BDNF gene.

Clinical Features

Gul et al. (2002) described a patient with the WAGR syndrome combined with severe obesity and found reports of 2 such patients (Marlin et al., 1994; Tiberio et al., 2000). Their patient and the patient of Marlin et al. (1994) had deletion of 11p14-p12. They suggested the existence of a gene in the 11p14-p12 region responsible for obesity and proposed the acronym WAGRO (O for obesity) for the association of WAGR with obesity.

Bremond-Gignac et al. (2005) reported a patient demonstrating WAGRO, which they stated had previously been reported in 4 cases.

Molecular Genetics

Because of reports implicating BDNF (113505) in energy homeostasis in humans, Han et al. (2008) hypothesized that the subphenotype of hyperphagia and obesity seen in a subgroup of patients with WAGR syndrome is attributable to deletions that induce haploinsufficiency of BDNF. Han et al. (2008) studied the relationship between genotype and body mass index (BMI) in 33 patients with WAGR syndrome who were recruited through the International WAGR Syndrome Association. The extent of each deletion was determined with the use of oligonucleotide comparative genomic hybridization. Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions. These patients had significantly higher BMI Z scores throughout childhood than did patients with intact BDNF: mean +/- standard deviation (SD) Z score at 8 to 10 years of age, 2.08 +/- 0.45 in patients with heterozygous BDNF deletions, versus 0.88 +/- 1.28 in patients without BDNF deletions; P = 0.03. By 10 years of age, 100% of the patients with heterozygous BDNF deletions (95% confidence interval 77 to 100) were obese (BMI greater than 95th percentile for age and sex) as compared with 20% of persons without BDNF deletions (95% confidence interval, 3 to 56; P less than 0.001), a rate that Han et al. (2008) noted was similar to that reported in the general pediatric population. The critical region for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF. Serum BDNF concentrations were approximately 50% lower among the patients with heterozygous BDNF deletions (P = 0.001). Although many other genes lie in the interval between WT1 and BDNF, only patients without BDNF deletions were of normal weight.