A Rare De Novo Nonsense Mutation in Otx2 Causes Early Onset Rod-Cone Dystrophy and Pituitary Dysfunction

Abstract

Purpose: : To describe the clinical findings of a patient with an early onset retinal dystrophy and a novel mutation in OTX2, and contrast these findings with previously reported cases.

Methods: : A panel of 142 patients with a diagnosis of Leber congenital amaurosis (LCA) or early onset retinal dystrophy (EORD) was screened by direct sequencing for mutations in OTX2. All patients had a detailed ophthalmic examination including full field electroretinography (ERG), and retinal imaging.

Results: : Only one mutation in OTX2 was identified. A novel heterozygous S138X stop mutation was identified in a 7 year old male with an infantile onset retinal dystrophy. The mutation was not present in either parent. There was a history of failure to thrive in infancy, poor feeding, and growth hormone deficiency. Poor vision and nyctalopia were present from the first year of life. Fundoscopy revealed a hyperpigmented peripapillary ring with a fine granular pigmentation of the RPE throughout the fundus. The dark adapted bright flash ERG had an electronegative waveform and photopic ERGs had a low b:a ratio. The ERGs were thus consistent with generalized rod and cone system dysfunction at a level that was primarily post-phototransduction or inner retinal. Visual function has remained stable to date.

Conclusions: : Mutations in OTX2 have been reported in association with major developmental malformations of the eye and retinal dystrophies such as LCA. This case adds further support for a role of OTX2 in retinal development and highlights a further retinal dystrophy phenotype seen in association with mutations in OTX2.

Keywords: retinal degenerations: hereditary • genetics • development