PAX6 aniridia and interhemispheric brain anomalies

Abstract

Purpose: To report the clinical and genetic study of patients with autosomal dominant aniridia.

Methods: We studied ten patients with aniridia from three families of Egyptian origin. All patients underwent full ophthalmologic, general and neurological examination, and blood drawing. Cerebral magnetic resonance imaging was performed in the index case of each family. Genomic DNA was prepared from venous leukocytes, and direct sequencing of all the exons and intron-exon junctions of the Paired Box gene 6 (PAX6) was performed after PCR amplification. Phenotype description, including ophthalmic and cerebral anomalies, mutation detection in PAX6 and phenotype-genotype correlation was acquired.

Results: Common features observed in the three families included absence of iris tissue, corneal pannus with different degrees of severity, and foveal hypoplasia with severely reduced visual acuity. In Families 2 and 3, additional findings, such as lens dislocation, lens opacities or polar cataract, and glaucoma, were observed. We identified two novel (c.170-174delTGGGC [p.L57fs17] and c.475delC [p.R159fs47]) and one known (c.718C>T [p.R240X]) PAX6 mutations in the affected members of the three families. Systemic and neurological examination was normal in all ten affected patients. Cerebral magnetic resonance imaging showed absence of the pineal gland in all three index patients. Severe hypoplasia of the brain anterior commissure was associated with the p.L57fs17 mutation, absence of the posterior commissure with p.R159fs47, and optic chiasma atrophy and almost complete agenesis of the corpus callosum with p.R240X.

Conclusions: We identified two novel PAX6 mutations in families with severe aniridia. In addition to common phenotype of aniridia and despite normal neurological examination, absence of the pineal gland and interhemispheric brain anomalies were observed in all three index patients. The heterogeneity of PAX6 mutations and brain anomalies are highlighted. This report emphasizes the association between aniridia and brain anomalies with or without functional impact, such as neurodevelopment delay or auditory dysfunction.

Figure 1

Pedigrees and mutation sequences of the three Egyptian families with autosomal dominant aniridia. Male and female subjects are represented by squares and circles, respectively, and affected family members have darkened symbols.

Figure 2

Slit-lamp photographs. A: Right eye of patient II-7 from Family 1. Note the significant, heavy, corneal vascularization sparing the nasal area. The iris base is very thin, almost invisible, a typical feature of aniridia. The patient was aphakic since cataract surgery performed in childhood. Best-corrected visual acuity was 0.1. B: Right eye patient III-4 from Family 1 showing heavy corneal vascularization (pannus) and superior dislocation of the lens. Almost no iris residual tissue is visible, as typically seen in aniridia. Note as well the small anterior polar cataract and the associated faint peripheral cortical opacities. C and D: Right and left eye of patient IV-3 from Family 2. Note the bilateral posterior polar cataract shaped like the petals of a flower and the superior lens dislocation. E and F: Fundus photographs. Right and left eye of patient IV-1 from Family 2. Foveal hypoplasia is observed with macular pigment epithelium alterations.

Figure 3

Axial cerebral T2-weighted magnetic resonance images. A: Patient III-1 from Family 1. Dashed arrow: severe hypoplasia of the anterior commissure. Arrow head: normal posterior commissure. Lower arrow: absence of the pineal gland. B: Normal magnetic resonance imaging (MRI) images. Dashed arrow: normal anterior commissure. Arrow head: normal posterior commissure. Lower arrow: normal pineal gland. C:  Patient IV-3 from Family 2. Dashed arrow: normal anterior commissure. Arrow head: absent posterior commissure. Lower arrow: absent pineal gland.

Figure 4

Coronal cerebral T2-weighted magnetic resonance images. A: Patient I-1 from Family 3. Dashed arrow shows severe hypogenesis of the corpus callosum with small amount of remnant tissue localized at the virtual connection between the genu and the body of the corpus callosum; arrow head shows the atrophic optic chiasm. B: Normal MRI images. Dashed arrow shows normal corpus callosum and arrow head shows normal optic chiasm. C: Patient I-1 from Family 3. Dashed arrow shows lateral callosal bundles of Probst, which are hemispheric connection fibers that did not cross the midline and that are seen in callosal dysgenesis. Superomedial margins of the lateral ventricles are indented by the Probst bundles. Arrow head shows remnants of the corpus callosum. Lower arrow shows normal posterior commissure. D: Normal MRI image with dashed arrow pointing normal corpus callosum.