Sir,

Aniridia is an autosomal dominant eye disorder caused by PAX6 gene mutations.1, 2 The disease is characterized by congenital absence of the iris with significant loss of vision due to foveal hypoplasia.3 Here we report a case, in which a rare PAX6 mutation causes aniridia with mild visual impairment.

Case report

A 4-month-old female without family history of ocular disorder was referred to our hospital for dilated pupils with photophobia. The parents noticed saccadic eye movements that were prominent in the first weeks of life and tended to decrease gradually. The ophthalmological examination, conducted in a quiet and cooperative child, was carried out without anaesthesia. Slit lamp observation showed bilateral iris hypoplasia with clear corneas and lenses. A horizontal nystagmus of low amplitude was noticed and binocular visual acuity, assessed using Teller acuity cards, was estimated to be 3/60. Intraocular pressure, obtained using a Perkins tonometer, was 8 mm Hg in both the eyes. The fundus examination did identify neither optic nerve abnormality nor foveal hypoplasia, but macular observation was difficult to perform because of nystagmus. At this time, a diagnosis of sporadic aniridia was established, and a mutation analysis of PAX6 was carried out. The genetic study revealed a heterozygous mutation [c.566-2A>G] in PAX6 intron 8–9 (http://www.ensembl.org, ENSG00000007372, ENST00000416339, ENSP00000405776) consisting in a splice site defect predicted to hamper proper splicing of the mRNA. None of the two unaffected parents carried this mutation. The patient was kept under review at 3-monthly intervals. Clinical follow-up revealed no dysmorphic features or psychomotor delay. On last examination, at the age of 2 years, the anterior segment presentation remained unchanged (Figure 1). Surprisingly, the nystagmus had completely disappeared and the best-corrected visual acuity, assessed using Teller acuity cards at the age of 18 months, increased to reach 6/18 in each eye. Cycloplegic refraction was −3.00/+1.25 × 165° (right) and −2.00/+1.25 × 20° (left). The eye fundus, obtained more easily because of disappearance of nystagmus, appeared to be normal without identifiable foveal hypoplasia.

Figure 1
figure 1

Anterior segment aspect observed in the 2-years-old patient carrying the [c.566-2A>G] mutation in the PAX6 gene. Slit-lamp biomicroscopy of right eye (R) and left eye (L) showing pronounced iris hypoplasia with clear corneas and complete absence of lens opacities.

Full size image

Comment

Due to early expression in the developing eye, the PAX6 gene is associated with various congenital ocular malformations, including aniridia, Peters' anomaly, keratitis, congenital cataract, optic nerve malformations, and microphthalmia.1, 2, 3, 4 Aniridia is considered as a haploinsufficiency ocular disorder, and is typically associated with PAX6 nonsense or frameshift mutations introducing a premature termination codon, whereas PAX6 missense mutations, of which the majority are located in the paired domain and result in impaired DNA binding, lead to non-aniridia phenotypes. The intriguing aspect of our observation lies in the mild degree of visual impairment with complete disappearance of nystagmus. The mutation encountered here has been reported only twice in human.4, 5 In the first case, the patient harbouring the mutation presented with aniridia, cataract, nystagmus, and corneal dystrophy.4 In the second case, the mutation was associated with complete iris defect, nystagmus, cataract, and strabismus.5 Although both phenotype descriptions claims for the presence of cataract and nystagmus, macular hypoplasia was not reported. At present, it is difficult to explain why such a PAX6 mutation consisting in a splice defect may cause variable clinical presentation with a possible relative preservation of the visual function. A possible explanation is that the predicted existence of an in frame cryptic splice site inside exon 9 or a variation in exon 9 skipping level could lead to a shortened protein partly deprived of transactivation domain instead of full haploinsufficiency.