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Education – Case 001


An 18 month old boy is referred to you with nystagmus and poor vision. Mother noticed he was not fixing and following or smiling at faces, and his eyes were constantly moving around. No other systemic features. They have had an array comparative genomic hybridisation (aCGH) at 6 months but this was negative with no deletions of 11p13 and WT1. No past medical history or drug history. He was born full-term with no complications and an unremarkable pregnancy. There was no family history or consanguinity reported. On examination, the vision was difficult to assess but 6/36 with both eyes open using Cardiff cards, intraocular pressure was 10 mmHg in both eyes, patient displays a clear cornea, iris hypoplasia and clear lens (Fig 1), fundus examination lacked a macular reflex (Fig 2) and foveal hypoplasia was confirmed on OCT (Fig 3). Ultrasound showed normal axial length.


Diagnosis is isolated aniridia, and PAX6 gene screening is undertaken which reveals a heterozygous nonsense variant in exon 10, c.781C>T p.(Arg261*). The parents were tested for segregation and this was negative so this is a de novo sporadic mutation. This child should be monitored by a paediatric ophthalmologist who can assess their visual development, referred to a general paediatrician if any concerns about systemic associations such as obesity, ataxia or sleep disorder and, as the vision is reduced, given access to a qualified teacher for children with visual impairment (QTVI) to address their current and future educational needs including their nursery placement. The patient requires regular follow-up to monitor progression of corneal disease, cataract and glaucoma with medical and surgical interventions where needed. Regular refraction and provision of tinted or photochromic lenses are required to reduce light sensitivity. Audiological evaluation may help identify and support early school age children with aniridia-associated central auditory processing deficits.

Genetic counselling:

If the parents want another child, they are not at any increased risk as this was not an inherited variant. This patient has a 50% chance of passing it to his offspring in the future (autosomal dominant) so he will benefit from future genetic counselling and family planning when he is an adult.

Clinical trials:

Nonsense suppression therapy is a new small molecule drug-based genetic treatment that can override the effect of in-frame nonsense variants. A drug called ataluren (or Translarna™) binds to the ribosome and weakens its fidelity to recognise a premature stop codon generated by the nonsense mutation, and so instead of translation terminating prematurely with a non-functional truncated protein, it overrides the signal and produced normal full-length functional protein in up to 20-25% levels or normal. There is a phase 2 randomized, double-masked, placebo-controlled study of ataluren in patients with aniridia caused by a nonsense mutations underway (NCT: 02647359). Children as young as 2 years old are eligible. Nonsense mutations account for up to 40% of the disease-causing mutations in aniridia. If this trial is successful, recruitment into a phase 3 study may be an option for the patient.
If the disease progresses and the child develops further complications with corneal keratopathy in the future, there are stem cell transplants in development for limbal stem cell deficiency.
Please follow this link for further updates on studies/trials linked to aniridia:

(Fig 1)  Fundus examination lacked a macular reflex

(Fig 2)  Foveal hypoplasia was confirmed on OCT

(Fig 3). Ultrasound showed normal axial length


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