Clinical and Molecular Characterization of Enhanced S-Cone Syndrome in Children

Abstract

IMPORTANCE Enhanced S-cone syndrome (ESCS) forms part of the differential diagnosis of night blindness in childhood.OBJECTIVE To report in detail the clinical phenotype and molecular genetic findings in a series of children with ESCS.DESIGN, SETTING AND PARTICIPANTS Nine children with ESCS from 5 families underwent full ophthalmic examination, electrophysiological testing, and retinal imaging at a genetic eye disease clinic of a tertiary referral eye hospital. Bidirectional Sanger sequencing of all exons and intron-exon boundaries of NR2E3 was performed. MAIN OUTCOMES AND MEASURESResults of ophthalmic examination and sequence analysis of NR2E3. RESULTS In total, 5 girls and 4 boys with a diagnosis of ESCS were included in the study. All patients had developed nyctalopia from early childhood. Visual acuity ranged from 0.00 to 1.20 logMAR (20/20 to 20/320 Snellen). All patients had hyperopia. Three patients had nummular pigmentary lesions along the arcades as typically seen in adults, 4 patients had mild pigmentary disturbance or white dots along the arcades, and 2 patients had a normal retinal appearance, although their fundus autofluorescence imaging demonstrated foci of increased autofluorescence along the arcades. Three patients had macular schisis-like changes on optical coherence tomography. Eight patients had electrophysiological testing at a mean age of 8.6 years (age range, 3-14 years), and in each patient the findings were consistent with the diagnosis of ESCS. Direct sequencing of NR2E3 identified 3 previously described mutations and 4 novel mutations. Seven patients were compound heterozygous for mutations in NR2E3, and 2 additional sibling patients were presumed to be homozygous for a missense change based on parental sequencing. CONCLUSIONS AND RELEVANCEIn this sample, children with ESCS had an early onset of night blindness and hyperopia but no nystagmus. Based on this study, children with ESCS may initially manifest a normal fundus appearance but later develop mottled retinal pigment epithelium change along the arcades, followed by the appearance of white dots in the same distribution. Fundus autofluorescence imaging is abnormal in children with a normal fundus appearance. The electrophysiological findings are pathognomonic and allow targeted molecular screening and a specific diagnosis.

Homozygosity for a Recessive Loss-of-Function Mutation of the NRL Gene Is Associated With a Variant of Enhanced S-Cone Syndrome

“…36 In addition, whitish subretinal dots, that appear hyperautofluorecent, have been described in ESCS. 15,20 Furthermore, the intraretinal hyperreflective foci demonstrated in OCT of patient A-1 seem similar to the ''rosette'' formation described in that report. 20 Patient B-1 had atrophic lesions along the arcades, fibrotic scars in the macula, as well as white and yellow dots.…”

“…14 Children with ESCS may initially manifest a normal fundus appearance, but later develop mottled RPE changes along the arcades, followed by the appearance of white dots in the same distribution. 15 Additional features may include foveal schitic changes, whitish retinal deposits, hyperpigmented lesions, torpedo-like atrophic lesions, posterior pole circumferential scars, and yellow dots in areas of relatively normal-appearing retina. 14,16,17 Hyperautofluorescence may occur within the arcades, associated with iovs.arvojournals.org j ISSN: 1552-5783 small areas of hyperpigmentation.…”

Cone Vision Changes in the Enhanced S-Cone Syndrome Caused byNR2E3Gene Mutations

“…4,7,29,31 Some of the fundus pathology also can be seen in other IRDs, hence leading to early confusion about clinical diagnosis before the unique functional mechanism was reported and later availability of molecular diagnostics. 1,13,24 Specific fundus abnormalities have not been clearly associated with specific NR2E3 genotypes.…”

Two-color pupillometry in enhanced S-cone syndrome caused by NR2E3 mutations

“…17,26 Thus, while two-color pupillometry could have clinical value in ESCS (e.g. in a child, who may be uncooperative for ERG, with atypical ESCS fundus findings 11,27,28,29 ), distinguishing among patients with RP and ESCS may be difficult on the basis of the PLR alone. Future modifications of the pupillometry backgrounds and stimuli, focusing on isolation of S-cones, 30,31,32,33 could elicit more specific or perhaps “super-normal” PLRs from ESCS patients.…”