Enhanced S-Cone Syndrome (ESCS) is an autosomal recessive progressive retinal degeneration characterized by loss of rod photoreceptors and abnormal proliferation of S-cones (short-wavelength blue-sensitive cones). It was first reported by Marmor and Jacobson in 1990 1).
The main causative gene is NR2E3 (15q22.32; nuclear receptor superfamily), with over 75 mutations identified 2). Mutations in NRL (Neural Retina Leucine zipper) can also produce the same phenotype 1, 3).
Goldmann-Favre syndrome (GFS) is considered a phenotype within the same disease spectrum as ESCS 3), and there have been reports of diagnostic confusion between the two for decades. García Caride et al. (2021) reported a case misdiagnosed as gyrate atrophy for 30 years, later confirmed as ESCS with a homozygous NRL: c.238C>T (p.Gln80*) mutation by genetic analysis 3).
In the normal retina, S-cones account for about 8–10% of all cones. In postmortem retinal tissue of ESCS, approximately 92% of photoreceptors were reported to be S-cones 2), highlighting the extent of abnormal proliferation.
They are currently considered phenotypes within the same disease spectrum. They share common NR2E3/NRL gene mutations and characteristic electroretinographic findings. There is substantial clinical overlap, and cases of diagnostic confusion have been reported in the past 3).
Fundus Findings
Coin-shaped pigmentation: A typical finding observed in approximately 85% of patients1).
Macular schisis: Splitting of the inner retinal layers. A key finding detectable by optical coherence tomography (OCT)1, 2, 4).
Tortuous retinal vessels: Abnormal vascular patterns2).
Posterior subcapsular cataract: Complicates advanced cases3).
Imaging and Test Findings
SD-OCT: Shows macular schisis, retinal thickening, and a characteristic double-layer structure1).
FAF (Fundus Autofluorescence): Characterized by a double hyperautofluorescent ring2).
Vitreous findings: Presence of vitreous cells1).
CME (Cystoid Macular Edema): Appears as a form of macular change1, 4).
da Palma et al. (2023) reported a 33-year-old female with ESCS presenting a double hyperautofluorescent ring on FAF2). This ring pattern was recorded in a patient with an NR2E3 mutation (p.Arg309Gly), and a definitive diagnosis was made through a 322-gene panel test.
Visual acuity decreases as the disease progresses, but there is considerable individual variation. Approximately 30% of patients have visual acuity of 20/100 (0.1) or worse. Macular schisis and cystoid macular edema (CME) are often major causes of visual decline. See also the section on “Diagnosis and Testing Methods”.
Overview of the causative genes and pathogenesis of ESCS.
| Gene | Chromosomal Locus | Main Function |
|---|---|---|
| NR2E3 | 15q22.32 | Suppression of cone genes in rod precursor cells |
| NRL | — | Transcriptional regulation of photoreceptor differentiation |
NR2E3 functions as a transcription factor that suppresses differentiation into cones in developing rod precursor cells 1). Mutations in this gene impair rod differentiation, leading to excessive differentiation of photoreceptors into S-cones, the “default pathway” 1). Over 75 pathogenic mutations have been reported in NR2E3 2), and the amino acid substitution p.Arg309Gly has been shown to reduce protein stability 2).
NRL mutations (e.g., c.238C>T; p.Gln80* homozygous) also produce the same phenotype 3). NRL is a transcription factor upstream of NR2E3 and is essential for inducing rod differentiation.
Because of the autosomal recessive inheritance pattern, cases have been reported in families with consanguineous marriage 4).
Electroretinography is the most important and characteristic test for diagnosing ESCS.
The following findings are considered pathognomonic for ESCS 1):
In atypical cases, normal rod ERG has been reported, with the first report of normal rod ERG in ESCS 2). The existence of such atypical cases highlights the importance of broad genetic testing.
| Test | Key Findings |
|---|---|
| SD-OCT | Macular schisis, retinal thickening, double-layer sign |
| FAF | Double hyperautofluorescent ring |
| AOSLO | Cone density 2–3 times normal |
AOSLO (adaptive optics scanning laser ophthalmoscopy) has visualized the cone mosaic in ESCS in vivo, showing cone density 2–3 times that of normal controls 1). However, total photoreceptor density is lower than normal, suggesting that only a subset of photoreceptors are converted to a cone-like phenotype 1).
The most important differential diagnosis is gyrate atrophy. Both conditions present with similar fundus findings (coin-shaped pigment deposits, night blindness), but in gyrate atrophy, blood ornithine levels are elevated. In ESCS, blood ornithine levels are normal, which is key for differentiation 3). In the case reported by García Caride et al., normal ornithine levels were overlooked, leading to a 30-year misdiagnosis 3).
Characteristic electroretinogram findings (similar scotopic and photopic waveforms, undetectable rod responses) are considered pathognomonic for ESCS 1). Confirming normal blood ornithine levels rules out gyrate atrophy, and genetic panel testing identifies NR2E3/NRL mutations 2, 3). In atypical cases, rod ERG may be preserved, making genetic testing more important.
There is currently no established curative treatment for ESCS. Management primarily focuses on symptomatic treatment of complications.
Pharmacotherapy
Carbonic anhydrase inhibitors (CAIs): First-line treatment for macular schisis and cystoid macular edema. Systemic acetazolamide 500 mg/day 2) or topical dorzolamide 4) are used.
Anti-VEGF therapy: Bevacizumab has been reported effective in cases complicated by type 3 neovascularization (NV3) 4).
Surgical Therapy
Maldonado et al. (2021) reported that in an ESCS patient with progressive vision loss (20/200), after diagnosing Type 3 neovascularization, eight injections of bevacizumab improved and stabilized visual acuity to 20/50 4). In this case, cystoid macular edema was also managed with dorzolamide eye drops 4).
Carbonic anhydrase inhibitors (CAIs) are first-line treatment. Systemic acetazolamide 2) or topical dorzolamide 4) can reduce schisis. Steroids are reported to be ineffective 1) and are not recommended. Anti-VEGF therapy is added when Type 3 neovascularization is present.
The central mechanism of ESCS pathogenesis is impaired rod differentiation due to loss of function of NR2E3/NRL.
In normal development, retinal progenitor cells have a “default pathway” that differentiates into cones (including S-cones). NRL diverts this pathway toward rods, and NR2E3 further stabilizes rod-specific gene expression, achieving the normal photoreceptor ratio (95% rods, 5% cones). When NR2E3 or NRL mutations occur 1):
Meanwhile, AOSLO observations show that cone density is increased 2-3 times normal, but total photoreceptor density is lower than normal 1). This indicates that only a portion of photoreceptors are converted to cone type. It is suggested that remaining photoreceptors may include hybrid photoreceptors with both rod and cone features, and similarity to rd7 mice (NR2E3-deficient model) has been noted 1).
Maldonado et al. (2021) reported multimodal evidence of type 3 neovascularization (intraretinal neovascularization) in ESCS 4).
On SD-OCT, 78% of hyperreflective foci detected within the outer nuclear layer (ONL) were subsequently confirmed as precursor lesions of type 3 neovascularization 4). This finding, combined with blood flow assessment by OCT-A, contributes to early detection of neovascularization.
Retinal progenitor cells inherently possess a “default pathway” to differentiate into S-cones. Normally, NRL and NR2E3 redirect this pathway toward rod differentiation. When mutations occur in these genes, the redirection fails, and progenitor cells over-differentiate as default S-cones 1). As a result, rods are almost completely absent, and S-cones occupy most of the retina.
Ammar et al. (2021) used AOSLO to visualize the in vivo cone mosaic in ESCS patients in detail for the first time 1).
Cone density measured by AOSLO was 2–3 times that of normal controls, while total photoreceptor density was lower than normal 1). In young patients, the layered structure of the central retina was histologically preserved. This finding suggests that functional tissue that could be a target for future gene therapy may remain.
da Palma et al. (2023) diagnosed an atypical case of ESCS using a 322-gene panel test 2). In this case, the electroretinogram showed preserved rod responses (first report of ESCS with normal rod ERG), making diagnosis based solely on clinical findings difficult. Comprehensive gene panel testing was shown to contribute to improved diagnostic accuracy in atypical cases.
García Caride et al. (2021) identified a novel NRL mutation in a case of ESCS with a homozygous NRL c.238C>T (p.Gln80*) mutation 3). This case had been managed as GFS for a long time, but genetic analysis reconfirmed that ESCS and GFS are on the same spectrum. This finding supports the significance of genetic testing in suspected GFS cases.
In young patients, cases where the central retinal layer structure is preserved have been confirmed1), and gene therapy is expected as a future candidate. The concept of NR2E3 gene replacement therapy has been studied in the rd7 mouse model, and basic research toward human application is ongoing.
