Diagnosis, Workup and Treatment

The patient underwent ultrasound of the kidneys, which did not identify any irregularity or mass.

Genetic analysis was initiated and revealed a normal male karyotype. Reflex testing to chromosomal microarray analysis did not identify submicroscopic dosage abnormalities. This ruled out a contiguous gene deletion in chr11p13, encompassing the Wilms tumor 1 gene (WT1) and PAX6 that would result in WAGR syndrome (Wilms tumor, Aniridia, Genitourinary abnormalities, and Retardation of growth and development). PAX6 gene sequencing identified a point mutation at nucleotide position 718, substituting a thymine for cytosine. This resulted in a nonsense mutation creating a premature stop codon and a truncated form of the protein. Further testing using exon level deletion/duplication analysis did not identify any intragenic deletions in the PAX6 gene or nearby WT1 (associated with Wilms tumor), DCDC1 or ELP4 genes (PAX6 enhancer genes).


Aniridia is a panocular disorder affecting the cornea, angle, lens and retina, among other ocular structures. The term aniridia is a misnomer, as it is rare for the iris to be completely absent. Aniridia is reported to have an incidence from 1:40,000-100,000.1,2 PAX6 gene mutations are implicated in almost all cases of congenital aniridia, however other loci have been reported.3 Two-thirds of aniridia cases are familial, while one-third are sporadic.1 Typically, hereditary aniridia is inherited in an autosomal dominant pattern and not associated with increased risk of Wilms tumor. Sporadic aniridia is more likely associated with 11p13 deletions involving PAX6 and the nearby WT1 locus resulting in WAGR syndrome, which necessitates urgent screening for early detection of renal malignancy.

Visual acuity with aniridia can range from mild impairment to legal blindness; however, the majority of patients with aniridia have visual acuities worse than 20/200 in adulthood.1 The decreased visual acuity is due to numerous mechanisms including keratopathy, cataract, glaucoma, nystagmus and macular hypoplasia.

Keratopathy occurs in 20 percent to 50 percent of aniridia cases1 and usually presents within the first decade of life. It is thought to be due in part to limbal stem cell deficiency and results in a vascularized, non-healing corneal surface, which is predisposed to recurrent erosions and ulcerations. Symptoms include decreased vision, dry-eye symptoms and photophobia.4 Management includes lubrication, autologous serum drops and amniotic membrane grafts.4 Artificial cornea keratoprostheses may have a role in selected cases due to the high rate of corneal graft failure.2

Patients with aniridia also require lifelong screening for glaucoma, which typically develops in childhood but also has an increased incidence in adulthood. Approximately 50 percent of patients develop glaucoma.5 Glaucoma may be due to trabecular dysgenesis, a progressive turning up of the iris stump over the trabecular meshwork or congenital aplasia of Schlemm’s canal. Medical management of aniridic glaucoma has demonstrated success rates as high as 40 percent.2 Nonetheless, many require surgery for this difficult-to-control form of glaucoma.

Cataract is also frequent in aniridia with a prevalence between 50 percent and 85 percent.6 Similar to our patient, these are initially noticed as lens abnormalities in infancy before developing into visually significant cataracts.1

Our patient presented with pendular horizontal nystagmus, which occurs in 81 to 95 percent of patients with aniridia.1 This nystagmus is thought to be secondary to macular hypoplasia, which has been documented to occur in approximately 75 percent of patients.1 Optic nerve hypoplasia is also found in approximately 10 percent of cases.2,8

Looking forward, STAR, the study of Ataluren in patients with aniridia is a Phase ll clinical trial that is currently recruiting patients with nonsense mutations in PAX6. Ataluren (formerly PTC124, PTC Therapetuics) promotes “read through,” which causes ribosomes to be more likely to continue translating protein through premature stop codons. Ataluren Phase ll clinical trials were found to be successful for cystic fibrosis due to nonsense mutations.9 In an aniridia mouse model with nonsense mutation in PAX6, Ataluren not only prevented disease progression but also reversed corneal, lens and retinal defects and restored electrical and behavioral responses of the retina postnatally.10,11 STAR is hoping to enroll 36 patients over the age of 2 and with confirmed nonsense mutation in PAX6 for treatment with Ataluren. STAR aims to be completed by 2018, and may offer new options in the treatment of aniridia.

Aniridia is a panocular condition that affects multiple tissues in the eye. Patients have decreased visual potential due to numerous mechanisms between keratopathy, cataract, glaucoma and macular hypoplasia. Aniridia is typically due to mutations in PAX6. Sporadic cases may be due to deletions involving PAX6 and the nearby WT1 locus thus predisposing to Wilms tumor.  REVIEW

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