A Case of Atypical WAGR Syndrome With Anterior Segment Anomaly and Microphthalmos

Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome) are caused by the deletion of chromosome 11p13, which includes the Wilms tumor gene (WT1) and the aniridia gene (PAX6) loci (MEM, No. 194070). We report a case of atypical WAGR syndrome with anterior segment anomaly and microphthalmos.

A 1-month-old boy had microphthalmos bilaterally. A microcornea with a corneal cyst in the right eye (axial length, 14.4 mm) (Figure 1A) and corneal opacity and absent anterior chamber in the left eye (axial length, 21.0 mm) (Figure 1B) seemed to be part of an anterior segment anomaly that includes the Peter anomaly. The vitreous cavities and posterior segments were normal. We examined the right eye with a small contact lens and light stimuli and obtained a normal response on the electroretinogram and in the left eye a subnormal response, suggesting retinal dysfunction. Wilms tumors developed bilaterally when the patient was 3 years old (Figure 1C). Because of a large tumor, we resected the right kidney; the left kidney underwent chemotherapy. The resected tumor had predominantly blastemal cells (Figure 1D). The child also had undescended testes and mental retardation. Analysis of G-banded prometaphase chromosomes identified deletion of chromosome 11p13-15.1 in 1 allele (Figure 2). Chromosomal analysis and physical findings were compatible with WAGR syndrome, but the ocular findings differed substantially.

Since the PAX6 gene was identified as a candidate gene for aniridia, numerous mutations of 11p13 have been reported in patients with aniridia. Studies have identified Pax6 mutations in numerous ocular anomalies, including the Peter anomaly, congenital cataract, and foveal hypoplasia.¹ In situ hybridization and immunohistologic examination identified multiple functions of the gene; the gene moves from the anterior to the posterior segments of the eye throughout development. Therefore, it is not surprising that ocular anomalies other than aniridia result from deletion of 11p13. Two other patients were described previously: a 2-month-old boy with a Peter anomaly and deletion of 11p13 who did not have Wilms tumor² and a 6-day-old boy with a Peter anomaly and Wilms tumor in whom chromosomal analysis was not undertaken.³ A 3-month-old boy with duplication of 11p13 had microphthalmia.⁴ Genetically similar mice with multiple copies of Pax6 have a microphthalmic phenotype,⁵ indicating gene dosage affects normal function.

PAX6 mutations in aniridia are usually nonsense, frameshift, or splicing errors in 1 allele, which result in a truncated protein, thus, haploinsufficiency of the gene products causes the aniridia phenotype, while few mutations in the Peter anomaly are missense¹. However, missense mutations recently found in patients with aniridia produce another route of haploinsufficiency. Thus, the relation between PAX6 gene dosage and phenotypic manifestations is still controversial. Affected individuals in a pedigree with aniridia who had the same PAX6 mutations have wide phenotypic variations. Because the PAX6 gene is influential in numerous ocular tissues throughout development, phenotypes may be reflected modifiers unlinked to the PAX6 gene cascade, cofactors of PAX6, or environmental conditions. Although aniridia and anterior segment anomalies including the Peter anomaly are distinct clinical entities, in our patient, aniridia resulting from deletion of one copy of PAX6 may be modified by these other factors and manifest corneal opacity, iridocorneal adhesion, and microphthalmos.

The authors have no proprietary interest in any aspect of this report.

Corresponding author: Noriyuki Azuma, MD, Department of Ophthalmology, National Children's Hospital, 3-35-31 Taishido, Setagaya-ku Tokyo, 154-8509 Japan (e-mail: nazuma@nch.go.jp).