Atypical presentation of CRB1 retinopathy

Early onset retinal dystrophy (EORD) is a clinical and genetically heterozygous disorder characterized by progressive photoreceptor degeneration resulting in severe visual impairment from early childhood. Mutations in the CRB1 gene are one of the commonest causes of EORD in European populations (Henderson et al. 2011; Bujakowska et al. 2012) and, to date, over 250 mutations have been reported in this gene. Although Crumbs-homologue-1 (CRB1) retino-pathy exhibits significant clinical variability (Bujakowska et al. 2012; Alves et al. 2014), there is a recognized phenotype that can help guide molecular genetic testing. Common clinical features include increased retinal thickness on optical coherence tomography (OCT), hypermetropic refractive error and deep nummular pigmentation. We present the case of a child who presented during screening for uveitis associated with juvenile idiopathic arthritis with macular oedema and was found to have an EORD and mutations in CRB1. An 18-month-old boy was referred from a rheumatologist for uveitis screening after a diagnosis of juvenile idiopathic arthritis was made. The child was experiencing left ankle pain, but there were no signs of uveitis and was in good health. There was no family history of arthritis or ocular disease. On examination, there were no signs or symptoms of uveitis, and fundoscopy was normal. Two years later in a routine follow-up appointment, although he remained asymptomatic at the time and still had no evidence of uveitis, he was found to have macula oedema in both eyes. A month later, he reported nyctalopia and central visual disturbance. Refraction revealed a +3.50/+0.50 × 86 and +4.50/+0.50 × 84 hypermetropic correction. Examination revealed mottled pigmentary changes in the retinal periphery (Fig. 1A,B) and macular thickening in both eyes. Optical coherence tomography (OCT) showed large hypo-reflective intraretinal spaces in the right eye and smaller cystic spaces in the left eye consistent with macular oedema (Fig. 1C–F). A full field electroretinogram revealed no recordable response in both eyes. Based on the phenotype described above, and in the absence of uveitis, a retinal dystrophy was suspected and the family underwent genetic counselling and panel-based genetic diagnostic testing (105 retinal dystrophy associated genes) (O'Sullivan et al. 2012). Two missense variants were detected in the CRB1 gene: c.584G>T, p.(Cys195Phe) and c.2843G>A, p.(Cys948Tyr). These changes have previously been described as disease causing (den Hollander et al. 1999, 2004) and are likely responsible for the patient's phenotype. The CRB1 gene encodes the CRB1 protein. This protein, localized above the adherens junctions in Müller glial cells, has a role in retinal development (Alves et al. 2014). Individuals with defects in CRB1 are likely to possess abnormal retinal architecture. Typically, there is severe retinal involvement with early macular changes. A previous study has also identified macular oedema in six of 11 cases (age range: 6–39 years; Bujakowska et al. 2012). This case highlights the need to be vigilant in our examination of patients when screening for uveitis for the presence of coexisting ocular disease. Furthermore, our findings add to and support the association between macular oedema and CRB1-related disease in a younger child. Crumbs-homologue-1 (CRB1) retinopathy should be considered as a differential in children presenting with bilateral macular oedema. Although carbonic anhydrase inhibitors have been previously used in such cases, there is no conclusive evidence of their efficacy. This report demonstrates the importance of the utility of a combined approach incorporating the assessment of retinal function (electrophysiology), retinal structure (fundus appearance and OCT) and genomic analysis in cases with early onset visual loss.