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Enhanced S Cone Syndrome (ESCS): for professionals


Overview

PrevalenceRare; less than 100 reported cases
InheritanceAutosomal recessive (with a unique autosomal dominant form linked to a specific missense variant)
Genes Involved (OMIM No.)NR2E3 gene (OMIM: #604485)
SymptomsNyctalopia, Reduced visual acuity, Photopsia
Ocular FeaturesMacular schisis: cystic changes in the macula, Macular atrophic changes, Yellow/white dots: hyperautofluorescent spots along vascular arcades and mid-peripheral retina, Nummular pigmentation: round-shaped pigment clumps temporally
Key InvestigationsOcular
Optical Coherence Tomography (OCT)
Fundus Autofluorescence (FAF)
Electroretinogram (ERG)
Additional S-Cone Testing ERG
Electro-oculogram (EOG)
Molecular DiagnosisGenetic testing for pathogenic variants in NR2E3
ManagementOcular: Regular ophthalmic monitoring, Refractive error correction (spectacles or contact lenses), Carbonic anhydrase inhibitors for macular schisis, Patient education on risk of choroidal neovascularisation, Amsler grid for home monitoring
Systemic: Genetic counselling, family planning advice, prenatal testing, preimplantation genetic diagnosis
Current ResearchResearch focused on understanding molecular mechanisms, developing gene therapies, improving diagnostic techniques, and investigating new treatments and management strategies to enhance quality of life for affected individuals

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Clinical phenotype

Enhanced S-Cone Syndrome (ESCS) is a rare inherited retinal dystrophy characterised by an overabundance of S-cone photoreceptors and a lack of rod photoreceptors. It is caused by biallelic variants in the NR2E3 gene, leading to a distinct retinopathy with childhood onset and slowly progressive symptoms.1,2

Presenting features

Ocular

  • Nyctalopia: The most common initial symptom, often presenting in the first decade of life.
  • Reduced visual acuity: Variably reduced, associated with hypermetropia.3,4
  • Photopsia: Flashes of light due to retinal changes.

Fundus

  • Macular schisis: Characteristic cystic changes in the macula. Present in approximately 40% of patients, associated with poorer visual outcomes.1,5
  • Macular atrophic changes: May accompany or follow macular schisis.
  • Yellow/white dots: Hyperautofluorescent spots at the level of the RPE, mainly along the vascular arcades and mid-peripheral retina.
  • Nummular pigmentation: Round-shaped pigment clumps at the RPE level, typically found temporally.

Genetics

Gene: NR2E3 (Nuclear Receptor Subfamily 2 Group E Member 3).

  • OMIM No.: #604485
  • Inheritance pattern: Autosomal Recessive (with a unique autosomal dominant form linked to a specific missense variant).
  • Function: NR2E3 encodes a photoreceptor-specific transcription factor crucial for rod photoreceptor development and the suppression of cone-specific genes. Loss of NR2E3 function results in an excess of S-cone photoreceptors and a lack of rod photoreceptors.6-9

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Ophthalmic examination: Macular schisis, yellow/white dots, and nummular pigmentation.
  2. Optical Coherence Tomography (OCT): Cystic changes in the macula, loss of outer retinal layers.5
  3. Fundus Autofluorescence (FAF): Areas of hyper- and hypo-autofluorescence indicating retinal changes.1
  4. Electrophysiological Testing:
    • Electroretinogram (ERG): Absent rod function, abnormal responses dominated by S-cone mechanisms, delayed flicker responses.10
    • Additional S-Cone Testing: High amplitude responses to blue stimulus on orange background.
    • Electro-oculogram (EOG): Reduced light peak to dark trough ratio, indicating dysfunction of the RPE.
  5. Genetic testing: targeted panel testing for pathogenic variants in NR2E3. However, usually the diagnosis can be made from the S-cone sequence on ERG.

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Diagnosis

Diagnosis of ESCS involves a combination of clinical evaluations, detailed ocular imaging, electrophysiological testing, and genetic analysis to confirm NR2E3 mutations.

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Differential Diagnoses

  • Other retinal dystrophies: Such as retinitis pigmentosa, which also involve night blindness but differ in genetic and electrophysiological profiles.
  • Goldmann-Favre syndrome: Closely related to ESCS with similar clinical and genetic features.

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Management

Management of ESCS is largely supportive, aiming to address the visual symptoms and monitor disease progression.

Ocular

  1. Regular ophthalmic monitoring: To track disease progression and manage complications.
  2. Refractive error correction: Use of spectacles or contact lenses for hypermetropia.
  3. Carbonic anhydrase inhibitors: For treating macular schisis, although efficacy is variable.11-13
  4. Patient education: Informing patients about the risk of choroidal neovascularisation and the importance of regular follow-up and home Amsler grid testing.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive comprehensive management of their condition (genetic testing and genetic counselling) and to have the opportunity to participate in clinical research.

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Current research

Research in ESCS is focused on understanding the molecular mechanisms underlying the disease, developing potential gene therapies, and improving diagnostic techniques. Clinical trials investigating new treatments and management strategies are ongoing, aiming to enhance outcomes and quality of life for affected individuals.

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Further information and support

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References

  1. de Carvalho ER, Robson AG, Arno G, Boon CJF, Webster AA, Michaelides M. Enhanced S-Cone Syndrome: Spectrum of Clinical, Imaging, Electrophysiologic, and Genetic Findings in a Retrospective Case Series of 56 Patients. Ophthalmol Retina. 2021;5(2):195-214. doi: 10.1016/j.oret.2020.07.008. Epub 2020 Jul 15. PMID: 32679203; PMCID: PMC7861019.
  2. Schorderet DF, Escher P. NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP). Hum Mutat. 2009;30:1475–1485.
  3. Jacobson SG, Marmor MF, Kemp CM, Knighton RW. SWS (blue) cone hypersensitivity in a newly identified retinal degeneration. Invest Ophthalmol Vis Sci. 1990;31(5):827-838.
  4. Khan AO, Aldahmesh M, Meyer B. The enhanced S-cone syndrome in children. BMJ Case Rep. 2009;2009.2008.1163.
  5. Yzer S, Barbazetto I, Allikmets R, et al. Expanded clinical spectrum of enhanced S-cone syndrome. JAMA Ophthalmol. 2013;131(10):1324-1330. doi:10.1001/jamaophthalmol.2013.4349.
  6. Haider NB, Mollema N, Gaule M, et al. Nr2e3-directed transcriptional regulation of genes involved in photoreceptor development and cell-type specific phototransduction. Exp Eye Res. 2009;89(3):365-372. doi:10.1016/j.exer.2009.04.006.
  7. Kanda A, Swaroop A. A comprehensive analysis of sequence variants and putative disease-causing mutations in photoreceptor-specific nuclear receptor. NR2E3. Mol Vis. 2009;15:2174–2184.
  8. Kobayashi M, Hara K, Yu RT, Yasuda K. Expression and functional analysis of Nr2e3, a photoreceptor-specific nuclear receptor, suggest common mechanisms in retinal development between avians and mammals. Dev Genes Evol. 2008;218:439–444.
  9. Littink KW, Stappers PTY, Riemslag FCC, et al. Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome. Genes (Basel). 2018;9(2):68. doi:10.3390/genes9020068.
  10. Tsang SH, Sharma T. Enhanced S-Cone Syndrome (Goldmann-Favre Syndrome). Adv Exp Med Biol. 2018;1085:153-156. doi: 10.1007/978-3-319-95046-4_28. PMID: 30578501.
  11. Bušić M, Bjeloš M, Bosnar D, Ramić S, Bušić I. Cystoid macular lesions are resistant to topical dorzolamide treatment in enhanced S-cone syndrome child. Doc Ophthalmol. 2016;132(1):67-73. doi:10.1007/s10633-016-9527-0.
  12. Hajali M, Fishman GA. Dorzolamide use in the management of macular cysts in a patient with enhanced s-cone syndrome. Retin Cases Brief Rep. 2009;3(2):121-124.
  13. Genead MA, Fishman GA, McAnany JJ. Efficacy of topical dorzolamide for treatment of cystic macular lesions in a patient with enhanced S-cone syndrome. Doc Ophthalmol. 2010;121(3):231-240. doi:10.1007/s10633-010-9247-9.

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Updated on June 3, 2024
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