Third case of WAGR syndrome with severe obesity and constitutional deletion of chromosome (11)(p12p14)

To the Editor:

Wilms tumor (WT) is one of the more common solid tumors of childhood, with an incidence of about 1 in 100,000 and it occurs primarily in children between 3 and 6 years of age. A small fraction of WT occurs in association with aniridia, genitourinary abnormalities, and mental retardation, the “WAGR syndrome.” These cases are often accompanied by a constitutional deletion of all or part of band 11p13. This constitutional deletion provided the first clue to the location of a gene involved in the development of Wilms tumor: WT1. It is now known that the WAGR deletion encompasses a number of contiguous genes, including the aniridia gene, PAX 6, and Wilms tumor suppressor gene WT1.

Here we report a 13-year-old boy with mental retardation and a constitutional deletion of (11)(p12p14). He presented with multiple congenital anomalies that were consistent with the WAGR syndrome. Clinical presentation was associated with remarkable obesity, which is an infrequent finding of WAGR syndrome.

The 13-year-old boy was referred for cytogenetic and clinical evaluation because of the association of mental retardation with unilateral Wilms tumor. He was the first child born to nonconsanguineous parents with an unremarkable medical history. The boy was born at full term after a normal pregnancy and had normal physical growth parameters for a newborn. Congenital bilateral aniridia and cataract were diagnosed in the early postnatal period, and the cataract (left) was surgically removed (Fig. 1). At age 1 year, he was diagnosed to have unilateral (left) Wilms tumor, stage II and was nephrectomized. No relevant complications had occurred thereafter and no specific therapy was needed.

The patient had mental retardation and multiple minor anomalies. He presented with a narrow forehead and abundant hair. He had a prominent chin and “puffy” lower lip (Fig. 1). The right testis was hypoplastic. At age 13 years, he had a weight of 65 kg (97th centile) and a height of 144 cm (10–25th centile). At his last admission to the hospital at 16.5 years of age, his weight was 130 kg (greater than 97th centile), and height 160 cm (10th centile).

Metabolic tests including adrenocortical and pancreatic functions were all within normal limits. The karyotype, performed on peripheral blood lymphocytes according to high-resolution technique, showed 46,XY,del(11)(p12p14)(Fig. 2). Karyotype of both parents were normal.

The WAGR syndrome is characterized by congenital abnormalities including predisposition to Wilms tumor, aniridia, genitourinary malformations, and mental retardation. Karyotypic analysis demonstrates a deletion within the short arm of one copy of chromosome 11 at band p13 [Chao et al., 2000]. The WAGR syndrome constitutes a contiguous gene syndrome. Loss of one allele of the PAX 6 gene is responsible for aniridia, whereas loss or mutation of one WT1 allele results in the genitourinary defects, in addition to constituting the first event required for the development of Wilms tumor [Coppes and Williams, 1994; Grundy et al., 1995].

Severe obesity is not usually a feature described with WAGR association. However, we are aware of two previous reports: Marlin et al. [1994] presented a 6-year-old girl with del (11)(p12p14) who manifested the primary symptoms of WAGR syndrome as well as severe obesity [Marlin et al., 1994]. A similar observation was documented by Tiberio et al. [2000]. Occurrence of obesity in a case of familial aniridia has also been mentioned by Winter and Baraitser [1993].

Our patient presented with severe obesity and a constitutional deletion of band (11)(p12p14). Severe generalized obesity could not be explained by any metabolic or endocrine disorder. We, as well as Marlin et al. [1994] and Tiberio et al. [2000], suggest that obesity may constitute a clinical feature of del 11p and hypothesize the existence of a gene in the 11p12p14 region responsible for obesity. We also suggest the acronym WAGRO (O for obesity) for the association of WAGR plus obesity.