Sir,

Waardenburg syndrome (WS) is a congenital pigmentary anomaly that affects the eye, hair, and skin. It is accompanied by facial abnormalities and deafness.1 WS is clinically and genetically heterogeneous, and WS type 1 (WS1) is characterized by dystopia canthorum. WS1 results from mutations in the PAX3 gene.2 We report a patient with WS1 who presented with unilateral vision decrease and a novel mutation in the PAX3 gene.

Case report

A 54-year-old woman with heterochromia of the right iris noticed a decrease in her vision. She had dystopia canthorum, hypopigmentation of her eyelashes and skin, and unilateral hearing impairment. A diagnosis of WS1 was made. Her best corrected visual acuities were 0.09 OD and 1.5 OS with refractive errors of −16.0 diopters (D) OD and −5.5 D OS. Intraocular pressure was 11 mmHg OD and 12 mmHg OS. The right fundus appeared albinotic over the entire retina accompanied by chorioretinal atrophy in the posterior pole probably due to the high myopia (Figure 1). A B-scan ultrasonogram showed an elongated axial length of 28.1 mm in the right eye, and a normal appearing left eye with an axial length of 25.0 mm. Posterior staphyloma-like changes were not detected in both eyes. Optical coherence tomography revealed a thickened pigment epithelial layer under the macula, suggestive of a myopic macular scar from a possible choroidal neovascularization (Figure 2).

Figure 1
figure 1

Fundus photographs of a patient with Waardenburg syndrome. (a) Photograph of the right eye showing albinotic appearance and a chorioretinal atrophy in the posterior pole due to high myopia. (b) The left eye shows a conus temporal to the disc with normal appearing macula.

Full size image
Figure 2
figure 2

Optical coherence tomographic images of the right and left eye. (a) Optical coherence tomographic image of the right eye shows a thickened retinal pigment epithelial layer under the macula. (b) Optical coherence tomographic image of the left eye showing normal findings.

Full size image

After an informed consent was obtained, a search for mutations in the PAX3 gene was made from the DNA extracted from the peripheral blood. A novel A → C transversion was identified in exon 5 resulting in a tyrosine → serine change at codon 243 (Figure 3). This codon is located in a highly conserved homeodomain. The change was not observed in 191 healthy controls, and this codon is conserved in different species.

Figure 3
figure 3

Sequencing results of the patient (upper) and a normal control (lower). A heterozygous A → C transversion can be seen in exon 5 resulting in a tyrosine-to-serine change at codon 243.

Full size image

Comment

Most of the symptoms and signs of our patient were consistent with those reported for patients with WS1. However, even with more than 50 mutations in the PAX3 gene reported, none of the patients has been reported to have a myopic macular degeneration as seen in our patient. In WS, the refractive errors vary considerably from hyperopia to myopia.3 The PAX3 gene is a transcription factor that is expressed during embryonic development and is critically involved in the development of melanocytes.4 The similarity in the phenotypic expression of different point mutations in the PAX3 gene indicates that these mutations cause a complete loss of function. However, a recent study suggested that different point mutations tend to exhibit independent properties of DNA binding.5

The novel mutation found in this study is predicted to alter highly conserved tyrosine at codon 243, which plays a role in homeodomain DNA binding through a phosphate contact.5 Although further studies are required, it is possible that, owing to the different property of deficient melanocytes, this patient was vulnerable to choroidal neovascularization in association with the high myopia. In any case, ophthalmologists should be aware that patients with WS1 may also have myopic macular degeneration.