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

Bilateral Macular Schisis and Progressive Vision Loss in a Young Male with Compound Heterozygous NR2E3 Mutations: A 4-Year Follow-Up | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Bilateral Macular Schisis and Progressive Vision Loss in a Young Male with Compound Heterozygous NR2E3 Mutations: A 4-Year Follow-Up Xiaohong Chen, Sheng Zhang, Guanyu Chen, Yan Sun, Ling Lin, Yuxin Xia, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7553550/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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. NR2E3 mutation visual electrophysiology enhanced S-cone syndrome night blindness Cystoid macular edema Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Enhanced S-cone Syndrome (ESCS) is a rare autosomal recessive retinal disease The disease was first reported in 1990[1].The main pathogenic cause of ESCS is regarded as related to NR2E3 gene mutation. During embryonic development, both cones and rods are derived from the same multipotent progenitor cell population[2]. Transcription factors encoded by genes such as NR2E3, CRX, and NRL interact with each other to form polyprotene transcriptional regulatory complexes, which play a regulatory role in the differentiation and development of primitive progenitor cells into cones and rods[3, 4]. NR2E3 gene mainly plays a role in inhibiting the expression of cone specific genes and activating the expression of rod specific genes in the differentiation of photoelectron cells[5]. When mutations in the NR2E3 gene result in loss of function, Photoreceptor cells develop and differentiate into a nonfunctional hybrid state similar to S-cone cells, but L-cone, M-cone and rod cells are not express [3, 6, 7]. Because of the absence of rod cells, ESCS patients suffer from night blindness and vision loss at an early stage[8]. But there may be no obvious signs in the early stage of the fundus, as the disease progresses appear yellow and white spots, torpedo-like atrophy lesions, coin-like or massive pigmentation along the vascular arch occur with or without retinoschisis and retinal cystoid changes[1, 9]. Due to the absence of rod cells and a large number of abnormal cones, there was no obvious rod cell response on ERG. The waveform of LA3.0 and DA3.0 was similar, and the amplitude of the flickering light response at 30HZ was lower than the A-wave at DA3.0[10, 11]. NR2E3-associated diseases have no obvious gene-phenotypic correlation, and various phenotypes including Goldmann-Favre syndrome, ESCS and pigment-mass retinopathy can appear, and even the same mutation can show different phenotypes[12]. This case report describes the visual function of ESCS and electrophysiological changes, as well as the first reported heterozygous gene phenotypes (p.R311Q, p.R97H), which may contribute to further understanding of its pathogenesis and structural characteristics. Case reports A 20-year-old male presents with a self-reported decline in vision over the past four months affecting both eyes. He has a history of Lasek surgery in both eyes. Upon admission, his best corrected visual acuity was 20/30 in the right eye and 20/50 in the left eye. Slit-lamp examination revealed normal anterior segment and vitreous in both eyes, with no apparent pigmentary changes in the fundus(Figure 1 A.B). Visual field(Fig. 1C):The visual field demonstrated ring-shaped scotomata sparing the central and far peripheral fields, along with discrete paracentral scotomas adjacent to fixation in both eyes.Optical coherence tomography (OCT )(Fig. 1D) demonstrated increased total retinal thickness bilaterally, macular retinal schisis with cystoid edema, distinct retinal "double-layer changes" notably featuring hypertonic ministerial retina, thickened outer nuclear layer (ONL), indistinct boundary between inner nuclear layer (INL) and ganglion cell layer (GCL) in the inner retina, and partial loss of photoreceptors, specifically the inner/outer segment (IS/OS) connection. Fundus Fluorescein angiography (FFA)(Fig. 1E): revealed punctate hyperfluorescence in the posterior pole during the initial phase and mottled hyperfluorescence in the periphery during the late phase, with no apparent leakage. The initial diagnosis was bilateral cystoid macular edema, managed with two initial intravitreal anti-VEGF injections.Following surgery, macular edema in both eyes initially decreased, leading to improved visual acuity; however, it promptly recurred. To investigate the underlying cause, electrophysiological assessments including ERG were conducted. The patient's ffERG revealed a diminished DA.01 waveform, indicating compromised rod cell function. Notably, the dark adaptation waveform closely resembled that of light adaptation, with the light-adapted response lacking the typical sharp peak. Furthermore, the a-wave amplitude of LA3. exceeded that of the LA30HZ response, with a ratio greater than 1. Typically, in the general population, the LA30HZ response falls between the a-wave and b-wave of LA3.. Additionally, the a-wave generated by s-cone cells was overshadowed by the b-wave elicited by L and M-cone cells. VEP analysis demonstrated delayed P100 peak latency in both eyes, more pronounced in the left eye, with reduced amplitude in the left eye and normal amplitude in the right eye. Notably, N135 amplitude remained unchanged in both eyes. Binocular contrast analysis using FlashVEP revealed a diminished P2 amplitude in the left eye. Subsequent exploration of the patient's medical history was undertaken to elucidate these findings.The patient had a long history of night blindness(Fig. 2). Following consent from the patient and family, genetic testing revealed the presence of the 932C>932G>A (p.R311Q) and 290C>932G>A (p.R97H) mutations in two alleles of the NR2E3 gene. Subsequent genetic testing on the parents confirmed the inheritance of the mutated genes(Fig. 3). The diagnosis of Enhanced S-cone Syndrome was established based on the patient's ocular examination results and genetic findings. At the 4-year follow-up assessment, the patient exhibited progressive disease manifestations: - Visual Function Deterioration: - Best-corrected visual acuity: - Right eye: declined from 20/30 to 20/200 - Left eye: declined from 20/50 to counting fingers - Persistent nyctalopia symptoms - Electrophysiological Progression(Fig. 4): - Rod system: - Non-detectable scotopic DA .01 responses indicating complete rod dysfunction - S-cone dominance: - Blue flash ERG ( cd·s/m²): - Right eye: a-wave 75. μV, b-wave 130 μV - Left eye: a-wave 99.3 μV, b-wave 128 μV - Red flash ERG (photopic 3. cd·s/m²): - Right eye: a-wave 22. μV, b-wave 16.7 μV - Pathognomonic ratio: Blue/red b-wave amplitude ratio of 7.8:1 - Cone system abnormalities: - Bilateral reduction of 30 Hz flicker amplitudes to ≤17 μV - LA 3. a-wave amplitude exceeding 30 Hz flicker response by >300% Structural Deterioration: - Spectral-domain OCT findings: Progressive cystoid macular edema with central retinal thickness increase >150 μm - Extension of schisis cavities into perifoveal regions - Complete disruption of IS/OS junction in temporal macula After the 4-year follow-up period, there was no significant progression of cystoid macular edema in both eyes, and the best-corrected visual acuity remained stable. DISCUSSION NR2E3 serves as a master regulator of photoreceptor differentiation, promoting rod maturation while suppressing cone-specific gene expression. During retinal development, multipotent progenitor cells give rise to both photoreceptor subtypes, with S-cones emerging first, followed by M/L-cones and rods. While NR2E3 is dispensable for early progenitor cell differentiation, it is essential for rod maturation and cone suppression. Loss-of-function mutations lead to aberrant expression of phototransduction genes, resulting in the S-cone-dominant hybrid photoreceptors characteristic of ESCS. Immunohistochemical studies confirm this molecular phenotype, showing S-opsin overexpression with absent rhodopsin and disrupted retinal lamination. The phenotypic spectrum of NR2E3 mutations encompasses ESCS, Goldmann-Favre syndrome, and retinitis pigmentosa (RP) [12,13-15]. The encoded protein contains four functional domains, with pathogenic variants clustering in the highly conserved DNA-binding (DBD) and ligand-binding (LBD) domains [2]. Our patient's compound heterozygous variants (p.R311Q in LBD; p.R97H in DBD) likely impair dimerization and ligand interactions, consistent with previous reports of DBD/LBD mutations causing ESCS [13]. Notably, the relatively preserved rod function observed in some ESCS cases with heterozygous mutations may reflect residual activity of mutant NR2E3 through functional domains retained in heterodimers [16]. Diagnostic challenges arise from the variable phenotypic expression of ESCS. While classic findings include perivascular pigmentation and macular schisis, our patient presented atypically without fundus pigmentary changes. OCT demonstrated characteristic schisis and cystoid edema while sparing the RPE - a finding consistent with preserved photoreceptor viability. Electrophysiologically, the pathognomonic ERG pattern (superimposable LA/DA waveforms, reduced 30Hz flicker) confirmed S-cone dominance, while asymmetric VEP abnormalities correlated with the left eye's worse structural and functional impairment. The transient response to anti-VEGF therapy followed by edema recurrence highlights the complex pathophysiology of ESCS. The long-term visual stability observed during 4-year follow-up suggests that NR2E3-mutant photoreceptors may remain viable despite functional abnormalities, with vision loss primarily driven by secondary structural changes rather than photoreceptor apoptosis. This parallels previous reports of stable ESCS phenotypes [10] and informs prognostic counseling. This case expands the genotypic spectrum of ESCS with novel heterozygous NR2E3 variants and provides longitudinal functional data. While emerging therapies like gene editing hold promise [17], significant knowledge gaps remain regarding NR2E3's precise mechanisms and genotype-phenotype correlations. Further studies are needed to elucidate how specific mutation combinations affect protein function and clinical presentation. Declarations Ethics Statement Institutional Review Board approval was waived for this case report in accordance with local regulations. Written informed consent was obtained from the patient for publication of clinical details and images. Funding This work was supported by: Key Project of the 900th Hospital of Joint Logistics Support Force (Grant No. 2022D04) School Management Project on Clinical Research of Fujian University of Traditional Chinese Medicine (Program Number:XB2024246） Author Contributions Xiaohong Chen, Sheng Zhang,Guanyu Chen Investigation, Writing - Original Draft Yan Sun, Ling Lin, Yuxin Xia, YunPeng Wang: Formal Analysis, Data Curation WeiMing Yan, XiangRong Zheng,YanJin Chen: Conceptualization, Supervision Conflicts of Interest The authors declare no competing financial interests or personal relationships that could influence this work.All authors reviewed the manuscript. References Marmor MF, Jacobson SG, Foerster MH, Kellner U, Weleber RG. （1990）Diagnostic clinical findings of a new syndrome with night blindness, maculopathy, and enhanced S cone sensitivity. 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Li S, Datta S, Brabbit E, Love Z, Woytowicz V, Flattery K, Capri J, Yao K, Wu S, Imboden M, Upadhyay A, Arumugham R, Thoreson WB, DeAngelis MM.（2021）Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa. Gene Ther. 2021;28(5):223-41.https://doi.org/10.1038/s41434-020-0134-z Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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1","display":"","copyAsset":false,"role":"figure","size":368942,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eClinical findings for patient. Panel of figures: (A)Fundus photography; (B) Fundus autofluorescence photography(FAF); (C) Visual field ; (D) Optical coherence tomography; (E) Fundus fluorescein angiography (FFA)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7553550/v1/17cf15e22b0226829e64c589.png"},{"id":95808242,"identity":"a0e13779-4cf7-4f8b-9260-64abdc67a86b","added_by":"auto","created_at":"2025-11-13 08:49:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":129765,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA Both eyes VEP examination of the patient. the peak value of P100 in the graphic visual evoked potential (PVEP) test was delayed in both eyes, and more obvious in the left eye. B ERG examination of both eyes. It is suggested that the function of rods in both eyes is impaired. The maximum dark adaptation response and light adaptation showed similar broad wave forms。Note:ERG showing reduced rod response (DA0.01) and similar waveforms in dark/light adaptation (DA3.0/LA3.0)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVEP: 1° checkerboard, 98% contrast\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eERG: ISCEV standard protocols\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7553550/v1/c80ceb53f711fc1a9461e449.png"},{"id":95807813,"identity":"3778c1e8-c87e-4cf2-afe2-d56bd65f449f","added_by":"auto","created_at":"2025-11-13 08:49:11","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":177449,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA Genetic testing of the patients revealed the presence of 932c.932G\u0026gt;A (p.R311Q) and 290c.932G\u0026gt;A (p.R97H) missense mutations in two alleles on NR2E3, respectively. B.Father's sequencing chromatogram showing heterozygous c.290G\u0026gt;A (p.R97H) mutation in exon 3; Mother's sequencing chromatogram showing heterozygous c.932G\u0026gt;A (p.R311Q) mutation in exon 6. C Genetic sequencing of the patient's parents suggests that the patient's mutated genes are inherited from their parents.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNote:Arrows indicate mutant alleles. The proband inherited both variants in trans.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7553550/v1/d40b777198fcb9875b77793f.png"},{"id":95807747,"identity":"ab719bdb-269c-42e5-9aa5-01429cf61297","added_by":"auto","created_at":"2025-11-13 08:49:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":121008,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA Blue flash electroretinography；B Red flash electroretinography\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7553550/v1/b5617753272f8d50980ca961.png"},{"id":96245137,"identity":"35945ea1-294b-4777-9731-ca797b1b7979","added_by":"auto","created_at":"2025-11-19 07:19:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1568532,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7553550/v1/e9013df0-d467-4c34-80d9-c7f673acfe20.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Bilateral Macular Schisis and Progressive Vision Loss in a Young Male with Compound Heterozygous NR2E3 Mutations: A 4-Year Follow-Up","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEnhanced S-cone Syndrome (ESCS) is a rare autosomal recessive retinal disease The disease was first reported in 1990[1].The main pathogenic cause of ESCS is regarded as related to NR2E3 gene mutation. During embryonic development, both cones and rods are derived from the same multipotent progenitor cell population[2]. Transcription factors encoded by genes such as NR2E3, CRX, and NRL interact with each other to form polyprotene transcriptional regulatory complexes, which play a regulatory role in the differentiation and development of primitive progenitor cells into cones and rods[3, 4]. NR2E3 gene mainly plays a role in inhibiting the expression of cone specific genes and activating the expression of rod specific genes in the differentiation of photoelectron cells[5]. When mutations in the NR2E3 gene result in loss of function, Photoreceptor cells develop and differentiate into a nonfunctional hybrid state similar to S-cone cells, but L-cone, M-cone and rod cells are not express [3, 6, 7].\u003c/p\u003e\n\u003cp\u003eBecause of the absence of rod cells, ESCS patients suffer from night blindness and vision loss at an early stage[8]. But there may be no obvious signs in the early stage of the fundus, as the disease progresses appear yellow and white spots, torpedo-like atrophy lesions, coin-like or massive pigmentation along the vascular arch occur with or without retinoschisis and retinal cystoid changes[1, 9]. Due to the absence of rod cells and a large number of abnormal cones, there was no obvious rod cell response on ERG. The waveform of LA3.0 and DA3.0 was similar, and the amplitude of the flickering light response at 30HZ was lower than the A-wave at DA3.0[10, 11].\u003c/p\u003e\n\u003cp\u003eNR2E3-associated diseases have no obvious gene-phenotypic correlation, and various phenotypes including Goldmann-Favre syndrome, ESCS and pigment-mass retinopathy can appear, and even the same mutation can show different phenotypes[12]. This case report describes the visual function of ESCS and electrophysiological changes, as well as the first reported heterozygous gene phenotypes (p.R311Q, p.R97H), which may contribute to further understanding of its pathogenesis and structural characteristics.\u003c/p\u003e"},{"header":"Case reports","content":"\u003cp\u003eA 20-year-old male presents with a self-reported decline in vision over the past four months affecting both eyes. He has a history of Lasek surgery in both eyes. Upon admission, his best corrected visual acuity was 20/30 in the right eye and 20/50 in the left eye. Slit-lamp examination revealed normal anterior segment and vitreous in both eyes, with no apparent pigmentary changes in the fundus(Figure 1 A.B). Visual field(Fig. 1C):The visual field demonstrated ring-shaped scotomata sparing the central and far peripheral fields, along with discrete paracentral scotomas adjacent to fixation in both eyes.Optical coherence tomography (OCT )(Fig. 1D) demonstrated increased total retinal thickness bilaterally, macular retinal schisis with cystoid edema, distinct retinal \u0026quot;double-layer changes\u0026quot; notably featuring hypertonic ministerial retina, thickened outer nuclear layer (ONL), indistinct boundary between inner nuclear layer (INL) and ganglion cell layer (GCL) in the inner retina, and partial loss of photoreceptors, specifically the inner/outer segment (IS/OS) connection. Fundus Fluorescein angiography (FFA)(Fig. 1E): revealed punctate hyperfluorescence in the posterior pole during the initial phase and mottled hyperfluorescence in the periphery during the late phase, with no apparent leakage. The initial diagnosis was bilateral cystoid macular edema, managed with two initial intravitreal anti-VEGF injections.Following surgery, macular edema in both eyes initially decreased, leading to improved visual acuity; however, it promptly recurred.\u003c/p\u003e\n\u003cp\u003eTo investigate the underlying cause, electrophysiological assessments including ERG were conducted. The patient\u0026apos;s ffERG revealed a diminished DA.01 waveform, indicating compromised rod cell function. Notably, the dark adaptation waveform closely resembled that of light adaptation, with the light-adapted response lacking the typical sharp peak. Furthermore, the a-wave amplitude of LA3. exceeded that of the LA30HZ response, with a ratio greater than 1. Typically, in the general population, the LA30HZ response falls between the a-wave and b-wave of LA3.. Additionally, the a-wave generated by s-cone cells was overshadowed by the b-wave elicited by L and M-cone cells. VEP analysis demonstrated delayed P100 peak latency in both eyes, more pronounced in the left eye, with reduced amplitude in the left eye and normal amplitude in the right eye. Notably, N135 amplitude remained unchanged in both eyes. Binocular contrast analysis using FlashVEP revealed a diminished P2 amplitude in the left eye. Subsequent exploration of the patient\u0026apos;s medical history was undertaken to elucidate these findings.The patient had a long history of night blindness(Fig. 2). Following consent from the patient and family, genetic testing revealed the presence of the 932C\u0026gt;932G\u0026gt;A (p.R311Q) and 290C\u0026gt;932G\u0026gt;A (p.R97H) mutations in two alleles of the NR2E3 gene. Subsequent genetic testing on the parents confirmed the inheritance of the mutated genes(Fig. 3).\u0026nbsp;The diagnosis of Enhanced S-cone Syndrome was established based on the patient\u0026apos;s ocular examination results and genetic findings.\u003c/p\u003e\n\u003cp\u003eAt the 4-year follow-up assessment, the patient exhibited progressive disease manifestations: - Visual Function Deterioration: - Best-corrected visual acuity: - Right eye: declined from 20/30 to 20/200 - Left eye: declined from 20/50 to counting fingers - Persistent nyctalopia symptoms - Electrophysiological Progression(Fig. 4): - Rod system: - Non-detectable scotopic DA .01 responses indicating complete rod dysfunction - S-cone dominance: - Blue flash ERG ( cd\u0026middot;s/m\u0026sup2;): - Right eye: a-wave 75. \u0026mu;V, b-wave 130 \u0026mu;V - Left eye: a-wave 99.3 \u0026mu;V, b-wave 128 \u0026mu;V - Red flash ERG (photopic 3. cd\u0026middot;s/m\u0026sup2;): - Right eye: a-wave 22. \u0026mu;V, b-wave 16.7 \u0026mu;V - Pathognomonic ratio: Blue/red b-wave amplitude ratio of 7.8:1 - Cone system abnormalities: - Bilateral reduction of 30 Hz flicker amplitudes to \u0026le;17 \u0026mu;V - LA 3. a-wave amplitude exceeding 30 Hz flicker response by \u0026gt;300% Structural Deterioration: - Spectral-domain OCT findings: Progressive cystoid macular edema with central retinal thickness increase \u0026gt;150 \u0026mu;m - Extension of schisis cavities into perifoveal regions - Complete disruption of IS/OS junction in temporal macula After the 4-year follow-up period, there was no significant progression of cystoid macular edema in both eyes, and the best-corrected visual acuity remained stable.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eNR2E3 serves as a master regulator of photoreceptor differentiation, promoting rod maturation while suppressing cone-specific gene expression. During retinal development, multipotent progenitor cells give rise to both photoreceptor subtypes, with S-cones emerging first, followed by M/L-cones and rods. While NR2E3 is dispensable for early progenitor cell differentiation, it is essential for rod maturation and cone suppression. Loss-of-function mutations lead to aberrant expression of phototransduction genes, resulting in the S-cone-dominant hybrid photoreceptors characteristic of ESCS. Immunohistochemical studies confirm this molecular phenotype, showing S-opsin overexpression with absent rhodopsin and disrupted retinal lamination.\u003c/p\u003e\n\u003cp\u003eThe phenotypic spectrum of NR2E3 mutations encompasses ESCS, Goldmann-Favre syndrome, and retinitis pigmentosa (RP) [12,13-15]. The encoded protein contains four functional domains, with pathogenic variants clustering in the highly conserved DNA-binding (DBD) and ligand-binding (LBD) domains [2]. Our patient\u0026apos;s compound heterozygous variants (p.R311Q in LBD; p.R97H in DBD) likely impair dimerization and ligand interactions, consistent with previous reports of DBD/LBD mutations causing ESCS [13]. Notably, the relatively preserved rod function observed in some ESCS cases with heterozygous mutations may reflect residual activity of mutant NR2E3 through functional domains retained in heterodimers [16].\u003c/p\u003e\n\u003cp\u003eDiagnostic challenges arise from the variable phenotypic expression of ESCS. While classic findings include perivascular pigmentation and macular schisis, our patient presented atypically without fundus pigmentary changes. OCT demonstrated characteristic schisis and cystoid edema while sparing the RPE - a finding consistent with preserved photoreceptor viability. Electrophysiologically, the pathognomonic ERG pattern (superimposable LA/DA waveforms, reduced 30Hz flicker) confirmed S-cone dominance, while asymmetric VEP abnormalities correlated with the left eye\u0026apos;s worse structural and functional impairment.\u003c/p\u003e\n\u003cp\u003eThe transient response to anti-VEGF therapy followed by edema recurrence highlights the complex pathophysiology of ESCS. The long-term visual stability observed during 4-year follow-up suggests that NR2E3-mutant photoreceptors may remain viable despite functional abnormalities, with vision loss primarily driven by secondary structural changes rather than photoreceptor apoptosis. This parallels previous reports of stable ESCS phenotypes [10] and informs prognostic counseling.\u003c/p\u003e\n\u003cp\u003eThis case expands the genotypic spectrum of ESCS with novel heterozygous NR2E3 variants and provides longitudinal functional data. While emerging therapies like gene editing hold promise [17], significant knowledge gaps remain regarding NR2E3\u0026apos;s precise mechanisms and genotype-phenotype correlations. Further studies are needed to elucidate how specific mutation combinations affect protein function and clinical presentation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics Statement\u003c/p\u003e\n\u003cp\u003eInstitutional Review Board approval was waived for this case report in accordance with local regulations. Written informed consent was obtained from the patient for publication of clinical details and images.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by:\u003c/p\u003e\n\u003cp\u003eKey Project of the 900th Hospital of Joint Logistics Support Force (Grant No. 2022D04)\u003c/p\u003e\n\u003cp\u003eSchool Management Project on Clinical Research of Fujian University of Traditional Chinese Medicine (Program Number:XB2024246）\u003c/p\u003e\n\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eXiaohong Chen, Sheng Zhang,Guanyu Chen Investigation, Writing - Original Draft\u003c/p\u003e\n\u003cp\u003eYan Sun, Ling Lin, Yuxin Xia, YunPeng Wang: Formal Analysis, Data Curation\u003c/p\u003e\n\u003cp\u003eWeiMing Yan, XiangRong Zheng,YanJin Chen: Conceptualization, Supervision\u003c/p\u003e\n\u003cp\u003eConflicts of Interest\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interests or personal relationships that could influence this work.All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMarmor MF, Jacobson SG, Foerster MH, Kellner U, Weleber RG. （1990）Diagnostic clinical findings of a new syndrome with night blindness, maculopathy, and enhanced S cone sensitivity. Am J Ophthalmol. 1990;110(2):124-34. https://doi.org/10.1016/s0002-9394(14)76980-6\u003c/li\u003e\n\u003cli\u003eMollema N, Haider NB.（2010） Focus on molecules: nuclear hormone receptor Nr2e3: impact on retinal development and disease. Exp Eye Res. 2010;91(2):116-7. https://doi.org/10.1016/j.exer.2010.04.013\u003c/li\u003e\n\u003cli\u003eCheng H, Khanna H, Oh EC, Hicks D, Mitton KP, Swaroop A. （2004）Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors. Hum Mol Genet. 2004;13(15):1563-75. https://doi.org/10.1093/hmg/ddh173\u003c/li\u003e\n\u003cli\u003eMurro V, Mucciolo DP, Sodi A, Passerini I, Giorgio D, Virgili G, Rizzo S.（2019）Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy. Graefes Arch Clin Exp Ophthalmol. 2019;257(1):9-22. https://doi.org/10.1007/s00417-018-4161-z\u003c/li\u003e\n\u003cli\u003eToms M, Ward N, Moosajee M. （2023）Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3): Role in Retinal Development and Disease. Genes (Basel). 2023;14(7). https://doi.org/10.3390/genes14071325\u003c/li\u003e\n\u003cli\u003eCheng H, Khan NW, Roger JE, Swaroop A.（2011） Excess cones in the retinal degeneration rd7 mouse, caused by the loss of function of orphan nuclear receptor Nr2e3, originate from early-born photoreceptor precursors. Hum Mol Genet. 2011;20(21):4102-15. https://doi.org/10.1093/hmg/ddr334\u003c/li\u003e\n\u003cli\u003eCorbo JC, Cepko CL. （2005）A hybrid photoreceptor expressing both rod and cone genes in a mouse model of enhanced S-cone syndrome. PLoS Genet. 2005;1(2):e11. https://doi.org/10.1371/journal.pgen.0010011\u003c/li\u003e\n\u003cli\u003eGarafalo AV, Calzetti G, Cideciyan AV, Roman AJ, Saxena S, Sumaroka A, Choi W, Wright AF, Jacobson SG. （2018）Cone Vision Changes in the Enhanced S-Cone Syndrome Caused by NR2E3 Gene Mutations. Invest Ophthalmol Vis Sci. 2018;59(8):3209-19. https://doi.org/10.1167/iovs.18-24518\u003c/li\u003e\n\u003cli\u003eSharon D, Sandberg MA, Caruso RC, Berson EL, Dryja TP. （2003）Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration. Arch Ophthalmol. 2003;121(9):1316-23.https://doi.org/10.1001/archopht.121.9.1316\u003c/li\u003e\n\u003cli\u003ede Carvalho ER, Robson AG, Arno G, Boon CJF, Webster AA, Michaelides M. （2021）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. https://doi.org/10.1016/j.oret.2020.07.008\u003c/li\u003e\n\u003cli\u003eGreenstein VC, Zaidi Q, Hood DC, Spehar B, Cideciyan AV, Jacobson SG. （1996）The enhanced S cone syndrome: an analysis of receptoral and post-receptoral changes. Vision Res. 1996;36(22):3711-22.https://doi.org/10.1016/0042-6989(96)00073-9\u003c/li\u003e\n\u003cli\u003eHaider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, et al. （2000）Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet. 2000;24(2):127-31. https://doi.org/10.1038/72777\u003c/li\u003e\n\u003cli\u003eSchorderet DF, Escher P. （2009）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(11):1475-85. https://doi.org/10.1002/humu.21096\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a Caride S, L\u0026oacute;pez Guajardo L, Donate L\u0026oacute;pez J. （2021）Goldmann-Favre/Enhanced S Cone Syndrome, 30 years mysdiagnosed as gyrate atrophy. Am J Ophthalmol Case Rep. 2021;21:101028. https://doi.org/10.1016/j.ajoc.2021.101028\u003c/li\u003e\n\u003cli\u003eGeorgiou M, Robson AG, Fujinami K, de Guimar\u0026atilde;es TAC, Fujinami-Yokokawa Y, Daich Varela M, et al. （2024）Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes. Prog Retin Eye Res. 2024;100:101244. https://doi.org/10.1016/j.preteyeres.2024.101244\u003c/li\u003e\n\u003cli\u003e. Hayashi T, Gekka T, Goto-Omoto S, Takeuchi T, Kubo A, Kitahara K. （2005）Novel NR2E3 mutations (R104Q, R334G) associated with a mild form of enhanced S-cone syndrome demonstrate compound heterozygosity. Ophthalmology. 2005;112(12):2115. https://doi.org/10.1016/j.ophtha.2005.07.002\u003c/li\u003e\n\u003cli\u003e. Li S, Datta S, Brabbit E, Love Z, Woytowicz V, Flattery K, Capri J, Yao K, Wu S, Imboden M, Upadhyay A, Arumugham R, Thoreson WB, DeAngelis MM.（2021）Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa. Gene Ther. 2021;28(5):223-41.https://doi.org/10.1038/s41434-020-0134-z\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"NR2E3 mutation, visual electrophysiology, enhanced S-cone syndrome, night blindness, Cystoid macular edema","lastPublishedDoi":"10.21203/rs.3.rs-7553550/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7553550/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo characterize a novel NR2E3 mutation pair (p.R311Q/p.R97H) in Enhanced S-cone syndrome (ESCS) and its clinical trajectory.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultimodal 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis 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.\u003c/p\u003e","manuscriptTitle":"Bilateral Macular Schisis and Progressive Vision Loss in a Young Male with Compound Heterozygous NR2E3 Mutations: A 4-Year Follow-Up","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-13 08:15:30","doi":"10.21203/rs.3.rs-7553550/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7325b6f4-f55f-428f-bfb6-718a4dc51cb3","owner":[],"postedDate":"November 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-14T17:38:33+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-13 08:15:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7553550","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7553550","identity":"rs-7553550","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}