The nuclear receptor class 2, subfamily E, member 3 protein is encoded by the NR2E3 gene, which is uniquely expressed in the outer nuclear layer of the retina. In addition, there is some evidence that NR2E3 suppresses cone differentiation during embryogenesis. NR2E3 pathogenic variants are associated with three distinct phenotypes: enhanced S-cone syndrome (ESCS), Goldman–Favre syndrome, and retinitis pigmentosa (RP).
22.1.1 Enhanced S-Cone Syndrome
ESCS is a rare autosomal recessive (AR) inherited retinal dystrophy that has variable clinical presentation. In this condition, S-cones are the majority cone subtype, whereas in a normal adult retina S-cones represent approximately only 10% of total cones. Normal posterior pole retina associated with arcades is a rod-rich zone. In ESCS, cones replace these rods and affected individuals present with symptoms of nyctalopia and visual field constriction from an early age. Best corrected visual acuity ranges from 20/20 to 20/200. Fundus findings include nummular pigment clumping at the level of the retinal pigment epithelium (RPE) along the vascular arcades and in the midperiphery, midperiphery and macular yellow flecks, macular cystoid spaces (▶ Fig. 22.1), macular hyperpigmentation with foveal sparing, and chorioretinal atrophic changes. Vitreous cells, opacities, haze, and veils can be seen. Ophthalmic findings can be seen as early as 4 years of age.
Fig. 22.1 Macular intraretinal cystoid spaces in a patient with compound heterozygous mutations in NR2E3. Left image shows macular spoke-wheel pattern.
22.1.2 Goldmann–Favre Syndrome
The classic Goldmann–Favre phenotype includes vitreous liquefaction with fibrillar strands and veils, nyctalopia, and severely abnormal full-field electroretinogram (ffERG) in early childhood. Patients tend to be hyperopic. As the condition progresses, patients develop chorioretinal atrophy, pigmentary retinal degeneration, marked visual field loss, peripheral and macular retinoschisis, and subcapsular cataract.
22.1.3 Retinitis Pigmentosa
NR2E3 mutations have been implicated in progressive degeneration of rods and subsequent involvement of cones, with characteristic “bone spicule” midperipheral pigmentation of RP. Disease may be AR or autosomal dominant (AD). Affected individuals show a decline of cone function relatively late, at a time when rod function is already undetectable.
22.1.4 Clumped Pigmentary Retinal Degeneration
Some patients may present with a specific pattern called clumped pigmentary retinal degeneration, which is found in less than 1% of RP cases. This pattern is characterized by abnormal nummular pigment clumping in the midperiphery or in the region of the arcades.
22.2 Molecular Genetics
These phenotypes are caused by NR2E3 mutations although there are no clear genotype–phenotype associations. RP shows genetic heterogeneity.
22.3 Differential Diagnosis
22.3.1 Retinitis Pigmentosa
Mutations in NR2E3 can present as RP with the presence of nummular pigmentary clumping or subretinal fibrosis is often seen as part of NR2E3 RP.
22.3.2 Congenital Stationary Night Blindness (OMIM 310500; 300071; 257270; 613216)
Because of early nyctalopia, this condition may be confused with ESCS. Nevertheless, nystagmus is a hallmark feature of congenital stationary night blindness (CSNB), which is not present in ESCS.
22.3.3 X-Linked Juvenile Retinoschisis (OMIM 312700)
This condition, characterized by impaired vision and macular intraretinal cystoid spaces, may be difficult to distinguish from ESCS by optical coherence tomography (OCT). Juvenile X-linked retinoschisis (JXLR) occurs almost exclusively in males, making ESCS a primary differential in female patients with intraretinal cystoid spaces. Mutations in RS1 cause JXLR. Peripheral retinoschisis is also seen in many patients although this can also be seen in Goldman–Favre syndrome.
22.3.4 Other Disorders with Intraretinal Cystoid Spaces
Other disorders with intraretinal cystoid spaces include fenestrated sheen dystrophy, pathologic myopia, NR2E3 retinopathies, degenerative macular schisis, drug induced (niacin), vitreomacular traction, isolated foveomacular schisis, and a wide range of retinal dystrophies.
22.3.5 Cystoid Macular Edema
As opposed to the nonleaking intraretinal cystoid spaces of ESCS and other disorders, the clinical diagnosis of cystoid macular edema (CME) is made based on a pattern of late progressive hyperfluorescence (leakage) on intravenous fluorescein angiography (IVFA) often showing a perifoveal petaloid pattern. There is a wide range of causes including inflammation, diabetes, optic nerve pits, and other conditions including the genetic disorder AD CME.
22.3.6 Clumped Pigmentary Retinopathy
Some patients with this phenotype have mutations in CRB1 or TULP1.
22.3.7 Torpedo Maculopathy
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