In enhanced S-cone syndrome (ESCS), rods and red and green cone receptors are degenerated, but S-cones are enhanced (increased in number).

The NR2E3R311Q mutation can lead to retinitis pigmentosa, enhanced S-cone syndrome (ESCS), Goldmann-Favre syndrome, and clumped pigmentary retinal degeneration. The relationship between this mutation and various recessive inherited retinal degenerative disorders is unclear and complicates clinical diagnosis and treatment. In this study, we generated a mouse strain carrying the NR2E3R296Q mutation using CRISPR/Cas9 technology to simulate the NR2E3R311Q mutation in humans and investigate the influence of this missense mutation on the photoreceptor developmental profile and retinal maintenance. Retinal architecture and lamination were normal in NR2E3R296Q mice. Whorls and rosettes were not observed in the outer nuclear layer (ONL). Rod cell quantity developed normally, whereas a small amount of Rhodopsin was incorrectly located in the ONL. Blue cones were excessively produced at the dorsal retina, whereas green cone development was normal. Colocalization of Rhodopsin and Arrestin occurred in the retinas of NR2E3R296Q mice. Heterozygous NR2E3+/R296Q mice showed no evident abnormalities in retinal structure or photoreceptor development. Retinas of NR2E3R296Q mice underwent progressive degeneration starting in the early postnatal stage, which manifested as reduced ONL thickness and outer segment fragmentation. The dorsal retina, where redundant blue cones are generated, degenerated in a more advanced manner. At the molecular level, NR2E3 bound directly to the RXRG promoter, whereas the NR2E3 R296Q mutation significantly impaired binding, resulting in significantly decreased RXRG mRNA and protein expressions. In summary, we developed a novel mouse model exhibiting an ESCS-like phenotype, thus providing a novel NR2E3-RXRG signaling pathway for modulating photoreceptor development and retinal maintenance.

Goldmann-Favre syndrome (GFS) is a rare vitreoretinal degenerative disorder caused by mutations in the NR2E3 gene located on the short arm of chromosome 15. This condition, inherited in an autosomal recessive manner, was first described by Favre in two siblings, with Ricci later confirming its hereditary pattern. In GFS, rod photoreceptors are essentially replaced by S-cone photoreceptors. Enhanced S-Cone Syndrome (ESCS) and Goldmann-Favre syndrome are two distinct entities within the spectrum of retinal degenerative diseases, both caused by mutations in the NR2E3 gene. Despite sharing a common genetic basis, these conditions exhibit significantly different clinical phenotypes. ESCS is characterized by an excessive number of S-cones (blue-sensitive cones) with degeneration of rods and L-/M-cones, leading to increased sensitivity to blue light and early-onset night blindness. In contrast, GFS is considered a more severe form of ESCS, involving additional features such as retinal schisis, vitreous degeneration, and more pronounced visual impairment. GFS typically manifests in the first decade of life as night blindness (nyctalopia) and progressive visual acuity impairment. The clinical features include degenerative vitreous changes such as liquefaction, strands, and bands, along with macular and peripheral retinoschisis, posterior subcapsular cataract, atypical pigmentary dystrophy, and markedly abnormal or nondetectable electroretinograms (ERGs). Although peripheral retinoschisis is more common in GFS, central retinoschisis may also occur. Despite the consistent genetic basis, the phenotype of GFS can vary significantly among individuals. The differential diagnosis should consider diseases within the retinal degenerative spectrum, including retinitis pigmentosa, congenital retinoschisis, and secondary pigmentary retinopathy.

NR2E3 is a nuclear hormone receptor gene required for the correct development of the retinal rod photoreceptors. Expression of NR2E3 protein in rod cell precursors suppresses cone-specific gene expression and, in concert with other transcription factors including NRL, activates the expression of rod-specific genes. Pathogenic variants involving NR2E3 cause a spectrum of retinopathies, including enhanced S-cone syndrome, Goldmann-Favre syndrome, retinitis pigmentosa, and clumped pigmentary retinal degeneration, with limited evidence of genotype-phenotype correlations. A common feature of NR2E3-related disease is an abnormally high number of cone photoreceptors that are sensitive to short wavelength light, the S-cones. This characteristic has been supported by mouse studies, which have also revealed that loss of Nr2e3 function causes photoreceptors to develop as cells that are intermediate between rods and cones. While there is currently no available cure for NR2E3-related retinopathies, there are a number of emerging therapeutic strategies under investigation, including the use of viral gene therapy and gene editing, that have shown promise for the future treatment of patients with NR2E3 variants and other inherited retinal diseases. This review provides a detailed overview of the current understanding of the role of NR2E3 in normal development and disease, and the associated clinical phenotypes, animal models, and therapeutic studies.

Enhanced S-cone syndrome (ESCS), also known as Goldmann-Favre syndrome, is a retinal degeneration that presents in childhood and leads to progressive nyctalopia and visual field loss. In advanced cases, this degeneration can result in loss of central visual acuity. We describe the case of a 15-year-old boy with ESCS who presented with retinal detachment, a rare complication.