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Clinicopathologic Reports, Case Reports, and Small Case Series
December 2001

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

Arch Ophthalmol. 2001;119(12):1855-1856. doi:

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.

Report of a Case

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.

Figure 1.
A, View of the anterior segment
of the right eye shows microphthalmos with a cyst. B, View of the anterior
segment of the left eye shows corneal opacity and iridocorneal adhesion. C,
Computed tomography reveals solid masses in both kidneys (arrows) and medullary
extension that consists of a hypovascular component in the right kidney. D,
Histopathologic findings from the resected tumor show a predominance of blastemal
cells without epithelial components. The blastema is arranged in a serpiginous
pattern and is sharply circumscribed from the surrounding stromal elements
(hematoxylin-eosin, original magnification ×25).

A, View of the anterior segment of the right eye shows microphthalmos with a cyst. B, View of the anterior segment of the left eye shows corneal opacity and iridocorneal adhesion. C, Computed tomography reveals solid masses in both kidneys (arrows) and medullary extension that consists of a hypovascular component in the right kidney. D, Histopathologic findings from the resected tumor show a predominance of blastemal cells without epithelial components. The blastema is arranged in a serpiginous pattern and is sharply circumscribed from the surrounding stromal elements (hematoxylin-eosin, original magnification ×25).

Figure 2.
The G-banded prometaphase chromosomes
show deletion of chromosome 11p13-15.1. The (p) indicates the short arm of
the chromosome; (q), the long arm.

The G-banded prometaphase chromosomes show deletion of chromosome 11p13-15.1. The (p) indicates the short arm of the chromosome; (q), the long arm.

Comment

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).

References
1.
Medical Research Council Human Genetics Unit, The human PAX6 allelic variant database Web site. Available at: http://www.hgu.mrc.ac.uk/Softdata/PAX6. Accessibility verified July 18 2001;
2.
Hanson  IMFletcher  JMJordan  T  et al.  Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters' anomaly. Nat Genet. 1994;6168- 173Article
3.
Eiferman  RA Association of Wilms' tumor with Peters' anomaly. Ann Ophthalmol. 1984;16933- 934
4.
Aalfs  CMFantas  JAWenniger-Prick  LJJM  et al.  Tandem duplication of 11p12-11p13 in a child with borderline development delay and eye. Am J Med Genet. 1997;73267- 271Article
5.
Schedl  ARoss  ALee  M  et al.  Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities. Cell. 1996;8671- 82Article
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