Bilateral Macular Schisis and Progressive Vision Loss in a Young Male with Compound Heterozygous NR2E3 Mutations: A 4-Year Follow-Up

Purpose To characterize a novel NR2E3 mutation pair (p.R311Q/p.R97H) in Enhanced S-cone syndrome (ESCS) and its clinical trajectory. Methods A 20-year-old male with progressive nyctalopia and recurrent macular edema underwent comprehensive evaluation including spectral-domain OCT, full-field ERG, pattern/flash VEP, and whole-exome sequencing with familial segregation analysis. Results Multimodal imaging revealed bilateral macular schisis with cystoid edema but absent pigmentary changes. Electrophysiology confirmed diagnostic hallmarks: extinguished rod responses, LA/DA waveform superimposition (S-cone dominance), and reduced 30Hz flicker amplitudes. Genetic analysis identified compound heterozygous variants affecting functional domains (p.R97H in DBD; p.R311Q in LBD), previously unreported in ESCS. Anti-VEGF therapy provided transient anatomical improvement without sustained benefit. Conclusion This report (1) expands the NR2E3 mutational spectrum with novel DBD/LBD variants, (2) demonstrates that vision loss correlates with secondary edema rather than primary photoreceptor degeneration.