Introduction

Although named for its most clinically obvious manifestation, total or partial absence of the iris, aniridia is a panocular disorder. Abnormalities may involve any portion of the anterior segment; additionally, abnormalities of posterior ocular structures, namely foveal and optic nerve hypoplasia, may occur and in part or entirely be responsible for visual impairment.1, 2, 3, 4, 5, 6, 7 Although the occurrence of optic nerve hypoplasia in patients with aniridia is well described, knowledge regarding frequency is limited; the largest series specifically addressing optic nerve hypoplasia prevalence described its occurrence in nine of 12 subjects.7 Foveal hypoplasia has been suggested as a possible cause for hypoplasia of the optic nerve.2, 3, 4, 5 This study evaluates, in patients with aniridia, the prevalence of optic nerve hypoplasia and its relationship to foveal hypoplasia.

Methods

The medical records of 80 consecutive patients diagnosed with aniridia at or in outside offices of physicians serving The Cincinnati Eye Institute were reviewed. In total, 56 patients with aniridia (31 female, 25 male; mean age 33 years, range 2–74) met the following inclusion criteria: (1) an adequate view of the posterior pole was documented or implied by a detailed description of fundus examination findings, and (2) either the presence or absence of both optic nerve and foveal abnormalities were documented. In all, 54 subjects were binocular and two were monocular, having undergone unilateral enucleation for a blind painful eye secondary to elevated intraocular pressure. The diagnosis of optic nerve hypoplasia was based on the treating physicians' clinical judgment; in no case was optic disc diameter specifically measured. Foveal hypoplasia was defined as the absence of a visible foveal depression and reflex. The fundoscopic appearance of the macular vasculature was inconsistently documented. Moreover, angiography was not performed unless for an unrelated indication. Therefore, abnormal fovea vasculature was not utilized as a diagnostic criterion. The relationship of nerve and foveal hypoplasia was assessed by comparing the prevalence of foveal hypoplasia in patients with and without optic nerve hypoplasia, using Fisher's exact test.

Results

Optic nerve hypoplasia was found in six of 56 patients, 10. 7% (95% CI: 4.8–21.5%), occurring in both eyes of five binocular and one monocular patient. Table 1 summarizes the clinical findings. Six subjects had foveal hypoplasia. The prevalence of foveal hypoplasia was higher in aniridia patients with (3/6, 50%) than in those without (3/50, 6.0%) optic nerve hypoplasia. This difference approached but did not achieve statistical significance (P=0.10). Noteworthy, nystagmus was found in five (83%) of the patients with optic nerve hypoplasia. Conversely, 36 (72%) of the patients without nerve hypoplasia had nystagmus.

Table 1 Clinical findings in patients with aniridia and optic nerve hypoplasia
Full size table

Discussion

Visual impairment in patients with aniridia is usually multifactorial, making determination of the significance of a specific ophthalmic abnormality difficult. In many cases, this is compounded by the inability to quantify the degree of underlying amblyopia accurately. Patients with clear ocular media and poor vision are often assumed to have retinal dysfunction, which has been described in patients with aniridia.3, 4, 5, 6 Abnormal electroretinographic (ERG) findings were reported in 100% (11/11) of patients by Tremblay et al5 and 74% (14/19) of patients by Wu et al.6 Although the occurrence of retinal dysfunction is generally accepted, its aetiology is a source of debate. Foveal aplasia or hypoplasia, directly due to the PAX6 mutation, and phototoxicity, a result of the poorly developed iris, both likely occur and to varying degrees account for retinal dysfunction. In our study group, ERG testing was not routinely performed and the proportion of patients with retinal phototoxicity or subtle hypoplasia, not resulting in a complete loss of the foveal depression, cannot be accurately estimated. However, severe foveal hypoplasia, complete absence of a foveal depression and reflex, was observed in six patients, 10.7% (95% CI: 4.8–21.5%).

The number of patients with nystagmus in whom nerve or foveal abnormalities were not identified raises the question that some might have gone undiagnosed. In some cases, poor acuity (and nystagmus secondarily) might be due to causes such as light toxicity or amblyopia. Another explanation is that in some cases nystagmus is not due to a sensory deficit but occurs independently. As discussed above, foveal dysfunction, due to either subtle hypoplasia or light toxicity, with a normal gross anatomical appearance certainly cannot be excluded.

Consistent with previous reports, we observed the simultaneous occurrence of optic nerve and foveal hypoplasia in several patients. Based on this observation, others have proposed a causal relationship between foveal and optic nerve hypoplasia. However, our data suggest an alternate aetiology in some if not all patients, as 50% of optic nerve hypoplasia cases occurred independent of foveal hypoplasia. The aniridia gene, PAX6, codes for a 522 amino-acid protein, is expressed in the optic stalk/cup and lens placode, and contains three conserved domains, thought to regulate transcription of additional genes involved in ocular development.8, 9, 10, 11 PAX6 mutations have been implicated in multiple congenital ophthalmic abnormalities including isolated foveal hypoplasia, Peters anomaly, corneal dystrophies, and cataracts.8, 12, 13, 14 Moreover, PAX6 mutations have been reported to result in a wide variety of congenital optic nerve abnormalities including hypoplasia.8 Therefore, it seems likely that a PAX6 mutation, resulting in the aniridic phenotype, could be responsible for abnormal optic nerve development. Although foveal hypoplasia might, in some instances, contribute to optic nerve hypoplasia, given that PAX6 mutations have been reported to result in both isolated nerve and foveal hypoplasia, our observation of nerve hypoplasia occurring independent of marked foveal hypoplasia suggests that its occurrence in patients with aniridia is at least in part a direct result of the PAX6 mutation.

This study is limited by potential biases inherent in all retrospective investigations. Also, excluded subjects with severe anterior segment disease preventing adequate fundus examination might have a higher occurrence rate of posterior segment abnormalities, leading to an underestimation of optic nerve hypoplasia prevalence. Moreover, patients were not prospectively evaluated specifically for optic nerve and foveal hypoplasia. Exact measurements of optic disc size were not made. Angiographic evaluation and electrophysiological testing were not performed. Therefore, minor abnormalities were likely missed. However, subtle optic nerve hypoplasia, which is not apparent on examination, is likely to have limited clinical significance.

In closing, in our study population, clinically apparent optic nerve hypoplasia occurred in roughly 10% of patients with aniridia. It is likely a direct consequence of the PAX6 mutation and may occur independently or in association with foveal hypoplasia.