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Original Investigation |

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

Sarah Hull, MA, FRCOphth1,2; Gavin Arno, PhD1; Panagiotis I. Sergouniotis, PhD1,2; Peter Tiffin, FRCOphth3; Arundhati Dev Borman, BSc, MRCOphth1,2; Aman Chandra, BSc, FRCOphth1,2; Anthony G. Robson, MSc, PhD1,2; Graham E. Holder, MSc, PhD1,2; Andrew R. Webster, FRCOphth, MD1,2; Anthony T. Moore, MA, FRCOphth1,2
[+] Author Affiliations
1Inherited Eye Diseases, University College London Institute of Ophthalmology, London, England
2Moorfields Eye Hospital, London, England
3Sunderland Eye Infirmary, Sunderland, England
JAMA Ophthalmol. 2014;132(11):1341-1349. doi:10.1001/jamaophthalmol.2014.2343.
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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 Measures  Results 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 Relevance  In 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.

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Figure 1.
Range of Fundus Abnormalities in Pediatric Enhanced S-Cone Syndrome

A through C, Patient 5 has left eye normal fundus appearance (A and B) and abnormal fundus autofluorescence imaging with high-density foci (C). D through F, Patient 2.1 has right eye normal fundus appearance in 2006 (D), right eye fundus appearance in 2011 with retinal pigment epithelium mottling present (E), and right eye fundus autofluorescence imaging with high-density foci (F). G and H, Patient 1.3 has right eye confocal scanning laser imaging fundus appearance with retinal pigment epithelium mottling and a few white dots (G) and fundus autofluorescence imaging showing diffuse paracentral hyperfluorescence and small high-density foci along the arcades (H). I and J, Patient 1.2 has right eye confocal scanning laser imaging fundus appearance demonstrating white dots and extensive nummular pigmentation (I) and fundus autofluorescence imaging demonstrating diffuse paracentral hyperfluorescence, small high-density foci, and a hypofluorescent ring outside of the arcades (J).

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Figure 2.
Spectral-Domain Optical Coherence Tomography Scans (Infrared Images Are on the Left, and Tomographic Images Are on the Right)

A, Patient 5 has left eye normal macular optical coherence tomography. B, Patient 2.1 has right eye abnormal macular optical coherence tomography with intraretinal cysts. C, Patient 1.2 has right eye abnormal superior arcade optical coherence tomography demonstrating disorganized architecture and multiple hyperreflective lesions in the outer nuclear layer (white arrowhead).

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Figure 3.
Electrophysiological Testing in Enhanced S-Cone Syndrome

A, Full-field and pattern electroretinography in patient 2.1. Electroretinography shows findings pathognomonic of enhanced S-cone syndrome. The dark-adapted (DA) 0.01 response (rod specific) is bilaterally undetectable. The DA 3.0 and light-adapted (LA) 3.0 responses have the same simplified waveform and are markedly delayed. The 30-Hz flicker electroretinography is both delayed and of lower amplitude than the LA 3.0 response a-wave. Pattern electroretinography (PERG) is bilaterally delayed. B, Extended S-cone electroretinography from the right eye of patient 2.1. S-cone electroretinography is delayed and simplified compared with the normal control and is of high amplitude. The healthy individual with 5-millisecond (ms) and 10-ms stimulus duration shows an early component from M-cones and L-cones and a later component from S-cones. The patient lacks the M-cone and L-cone component. The 200-ms blue stimulus response shows some off activity, as occurs in some but not all patients with enhanced S-cone syndrome.4 The photopic on-off response in the patient (200-ms orange flash) is markedly reduced, demonstrates a simplified waveform, and shows delay in all components.

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