Meesmann Corneal Dystrophy Misdiagnosed as Refractory Dry Eye Disease: A case Report

Meesmann Corneal Dystrophy Misdiagnosed as Refractory Dry Eye Disease: A case Report | 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 Meesmann Corneal Dystrophy Misdiagnosed as Refractory Dry Eye Disease: A case Report Ahyan Ilman Qudsi, Jinding Pang, Qingfeng Liang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8973040/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 Background Meesmann epithelial corneal dystrophy (MECD) is a well-recognized autosomal-dominant epithelial disorder caused by keratin mutations and classically characterized by diffuse intraepithelial microcysts. However, when these microcysts are subtle on routine slit-lamp examination, the condition may closely mimic chronic dry eye disease, leading to delayed diagnosis and prolonged ineffective therapy. We report a familial case initially managed as refractory dry eye disease in which multimodal imaging and genetic analysis established the correct diagnosis and identified a previously unreported keratin 3 variant. Case presentation: A 55-year-old Chinese man with well-controlled type 2 diabetes presented with six months of bilateral ocular discomfort and progressive visual blur. Slit-lamp examination demonstrated a narrow tear meniscus and diffuse punctate epithelial erosions without obvious dystrophic features, and he was treated for presumed dry eye disease with lubricants, anti-inflammatory agents, and epithelial trophic therapy over several months without meaningful improvement. The persistence of epithelial irregularity despite therapy prompted re-evaluation, and pre-fluorescein retroillumination revealed numerous glistening intraepithelial microcysts across the interpalpebral cornea. In vivo confocal microscopy confirmed dense, sharply demarcated microcysts involving superficial and basal epithelial layers. Examination of his asymptomatic 30-year-old son disclosed similar bilateral microcystic changes. Targeted next-generation sequencing identified a heterozygous keratin 3 missense variant (c.1525G > C, p.Glu509Gln) in both individuals, with Sanger sequencing confirming familial segregation. The variant is absent from population databases and predicted to be deleterious by computational analysis, supporting the diagnosis of Meesmann epithelial corneal dystrophy. Conclusions MECD may masquerade as therapy-refractory dry eye disease when microcysts are inconspicuous on standard examination. Persistent epithelial changes despite optimized tear management should prompt retroillumination, in vivo confocal microscopy, and consideration of genetic testing. Early recognition prevents prolonged misdirected treatment and enables appropriate family counseling. Corneal dystrophy Meesmann dystrophy KRT3 gene mutation Diagnosis Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Meesmann epithelial corneal dystrophy (MECD) is a rare autosomal-dominant disorder of the corneal epithelium, marked by numerous punctate intraepithelial microcysts predominantly across the interpalpebral region 1 , 2 . Histopathological examination reveals epithelial vacuoles containing aberrant keratin aggregates, reflecting disrupted intermediate filament assembly within suprabasal epithelial cells. Clinical manifestations typically begin in early life, yet symptom severity is highly variable, ranging from mild ocular irritation to photophobia and transient visual blur 3 , 4 . Within families, incomplete penetrance and pronounced variability in expressivity are frequently observed 5 , 6 . Because early MECD changes can be subtle under routine diffuse illumination, affected individuals are occasionally misdiagnosed with severe dry eye disease (DED) or nonspecific epithelial keratopathy, delaying definitive diagnosis and appropriate genetic counseling 7 . In this context, pre-fluorescein retroillumination, epithelial-layer in vivo confocal microscopy (IVCM), and targeted genetic sequencing substantially enhance diagnostic specificity 5 , 8 . We describe a Chinese pedigree, initially managed as refractory DED, in which retroillumination and IVCM revealed a characteristic MECD microcystic phenotype. Genetic analysis identified a previously unreported heterozygous KRT3 missense variant, c.1525G > C, p.(Glu509Gln), affecting a residue recurrently implicated in MECD. We further discuss practical clinical discriminators and variant interpretation considerations within the broader spectrum of known KRT3 and KRT12 mutations. Case presentation Clinical Findings 55-year-old Chinese man with a ten-year history of well-controlled type 2 diabetes who presented on 17 June 2025 with a six-month history of bilateral ocular discomfort, including dryness, intermittent foreign-body sensation, and progressive visual blur. At presentation, uncorrected visual acuity was 0.03 in the right eye and 0.3 in the left eye. Slit-lamp examination revealed a narrow tear meniscus, mild bulbar hyperemia, and diffuse punctate epithelial erosions in both eyes. No focal epithelial opacities, subepithelial changes, or stromal abnormalities were observed at that stage. Based on the presenting symptoms and diffuse punctate epithelial staining, provisional diagnoses included conjunctivitis, dry eye disease, and age-related cataract. Initial therapy comprised topical gatifloxacin gel, 0.02% fluorometholone, recombinant bovine basic fibroblast growth factor, vitamin A palmitate gel, and 0.2% cyclosporine. Medication regimens were adjusted according to the patient’s clinical response at subsequent visits. A summary of findings across all follow-up visits, including symptom progression, slit-lamp features, and epithelial staining, is provided in Table 1 . Table 1 Summary of Serial Clinical Visits Prior to Definitive Diagnosis Date Key Clinical Findings Provisional Diagnosis Management June 17 Narrow tear meniscus; mild conjunctival injection; diffuse punctate epithelial staining Conjunctivitis / Dry eye / Cataract Sodium hyaluronate, cyclosporine, bFGF, vit A gel Jul 22 Meibomian gland plugs; persistent epithelial staining Keratitis / Dry eye Fluorometholone, levofloxacin, vit A gel Aug 26 Similar exam; no improvement Keratitis / Dry eye Continued topical therapy Sep 23 Persistent epithelial irregularity, stroma clear Bilateral epithelial keratopathy Observation Oct 21 Intraepithelial microcysts detected Suspected epithelial dystrophy IVCM and Genetic testing initiated including the son Over the subsequent months, the patient remained compliant with the prescribed therapy but reported no meaningful subjective improvement. Serial examinations demonstrated persistent punctate epithelial changes accompanied by stable tear-film abnormalities, and obstruction of several meibomian gland orifices was newly identified. Punctate staining continued to worsen, most prominently in the right eye, despite three months of uninterrupted treatment. With intensified lubrication, the staining showed modest reduction; however, the overall epithelial appearance remained consistent with a typical dry eye pattern. The discrepancy between symptoms, treatment duration, and the partial, inconsistent surface response raised concern that the initial diagnoses did not fully explain the underlying disease process. Figure 1 . Diagnostic imaging of Meesmann corneal dystrophy in the proband (II-1). Panels A and B show external photographs of both eyes, C and D show retro-illumination highlighting intraepithelial microcysts, E and F show fluorescein staining demonstrating milder punctate epithelial erosions after dry eye treatment, and G and H show in vivo confocal microscopy (IVCM) revealing hyperreflective intraepithelial microcysts and epithelial cell irregularities. A focused re-evaluation was performed four months after the initial visit. Retroillumination prior to fluorescein instillation revealed numerous small, glistening intraepithelial microcysts scattered across the interpalpebral zone of both corneas (Fig. 1 C-D). These lesions had not been detected during earlier examinations. Fluorescein staining was now minimal, suggesting that lubrication had smoothed the surface without addressing the underlying epithelial disruption. The observed microcyst pattern strongly suggested a hereditary epithelial abnormality, and MECD emerged as the leading consideration in the differential diagnosis. Given the emerging suspicion of a hereditary epithelial disorder, a structural assessment using IVCM was performed. The scans revealed a dense population of round and oval hyperreflective intraepithelial microcysts in both eyes, involving the superficial and basal epithelial layers. Smaller, tightly arranged microcysts predominated in the basal epithelium, while the superficial layer contained larger cystic spaces interspersed with hyperreflective cellular debris. This distribution and morphology correspond closely with the epithelial architecture reported in MECD. Representative images are shown in Fig. 1 G-H. Because the clinical findings suggested an inherited epithelial disorder, first-degree relatives were evaluated. The only available family member, the proband’s thirty-year-old son (III-1), who accompanied him to the clinic, underwent a comprehensive ophthalmic assessment. No additional relatives could be examined, as the proband’s father and paternal grandfather were deceased. Although asymptomatic, the son demonstrated numerous, uniform microcysts on retroillumination and denser, more tightly clustered microcysts on in vivo confocal microscopy compared with his father (II-1) (Fig. 2 C–D). Fluorescein staining revealed more pronounced punctate epithelial erosions than in his father (Fig. 2 C-F), likely reflecting the absence of prior dry eye therapy, while his IVCM findings were typical and closely mirrored those observed in his father (Fig. 2 G-H). Collectively, these observations underscore the bilateral, familial pattern of microcystic epithelial changes and support the inherited nature of the disorder. Genetic Findings Targeted next-generation sequencing using a corneal dystrophy panel identified a heterozygous KRT3 c.1525G > C (p.Glu509Gln) variant in both affected individuals. Sanger sequencing confirmed the heterozygous substitution in the proband (II-1) and his son (III-1), consistent with familial segregation (Fig. 3 ). Electropherograms displayed clear dual peaks (G/C) at the variant position, providing molecular evidence of co-segregation with the phenotype across two affected generations. The variant has not been previously reported in ClinVar or other publicly available databases and is absent from population datasets (gnomAD, ExAC). In silico analysis (REVEL = 0.82) predicts the variant to be deleterious. According to ACMG guidelines, it is currently classified as a Variant of Uncertain Significance (VUS), with supporting evidence including absence from population databases, computational predictions, and segregation with disease in the family. Notably, prior studies have repeatedly implicated substitutions at Glu509 within exon 7 of KRT3 as recurrent hotspots for MECD, including p.Glu509Lys and p.Glu509Asp, each associated with the classic microcystic epithelial phenotype. The involvement of the same residue suggests that additional evidence may justify reclassification of p.Glu509Gln to likely pathogenic in future updates. To contextualize, prior reports have identified seven distinct KRT3 variants and twenty-five KRT12 variants associated with Meesmann corneal dystrophy, with several studies highlighting substitutions at Glu509 in exon 7 of KRT3 (e.g., p.Glu509Lys, p.Glu509Asp) as recurrent hotspots linked to the classic microcystic epithelial phenotype 5 – 6 , 9 – 30 . The involvement of the same residue suggests that additional evidence may justify reclassifying p.Glu509Gln as likely pathogenic in future updates. Although formally classified as a variant of uncertain significance under ACMG/AMP guidelines, the cumulative evidence supports a likely pathogenic interpretation 31 – 33 . This assessment is based on its absence from population databases, a deleterious computational score (REVEL = 0.82), segregation across two affected family members, and close phenotypic concordance with previously reported MECD presentations 34 , 35 . Diagnostic Considerations The clinical presentation of MECD can closely resemble common ocular surface disorders, particularly dry eye disease (DED), which may lead to delayed or misdirected diagnosis. To clarify this overlap and identify key distinguishing features, we systematically compared multimodal imaging from our cohort of genetically confirmed MECD cases (Fig. 1 – 2 ) with imaging from clinically representative DED patient (Fig. 4 ). The distinguishing clinical and microstructural characteristics are summarized in Table 2 . Table 2 Key distinguishing features of MECD versus DED: clinical, staining, and microstructural correlates Feature MECD findings (clinical / imaging) DED findings (clinical / imaging) Diagnostic significance Diffuse slit-lamp (white-light) Subtle grey-white epithelial haze with focal surface irregularity and punctate microcystic changes; often symmetric and seen across affected family members. Figure 1 ,2. A-D Generalized epithelial roughening and granular surface irregularity without discrete microcysts; variable and often asymmetric. Figure 4 . A-B Presence of a bilateral, consistent microcystic haze across relatives favors MECD over DED. Retro-illumination Sharply demarcated, punctate areas of altered translucency corresponding to intraepithelial microcysts; discrete lucencies stand out against otherwise clear stroma. Figure 1 ,2. E-H Diffuse light-scattering from tear-film breakup and surface desiccation; lacks discrete cystic lucencies. Figure 4 . C-D Retro-illumination that reveals sharply circumscribed intraepithelial lucencies is highly suggestive of MECD. Fluorescein / vital-dye staining pattern Punctate staining that localizes to discrete areas of epithelial fragility overlying microcysts; staining is persistent and focal, reflecting underlying architecture. Figure 1 ,2. I-L Superficial, diffuse punctate erosions that fluctuate with blink and tear-film stability; more transient. Figure 4 . E-F Persistent, focal staining despite normal/near-normal tear metrics suggests structural epithelial disease (MECD) rather than purely tear-film instability. Temporal dynamics of staining Persistent, reproducible pattern over time and visits; does not markedly change with blink/tear-film manipulation. Variable; staining distribution changes with blink, environmental conditions and tear metrics. Lack of fluctuation with blink/tear interventions supports MECD. In vivo confocal microscopy (IVCM) Numerous sharply demarcated hyporeflective intraepithelial lacunae (microcysts) within a disrupted epithelial mosaic; lacunae may contain reflective debris and are bounded by irregular cell borders. Figure 1 ,2. M-P Diffuse epithelial hyperreflectivity and irregular superficial architecture without discrete intraepithelial lacunae/cysts. Figure 4 . G-H IVCM provides the most specific microstructural discriminator: discrete lacunae = MECD; diffuse hyperreflectivity without lacunae = DED. Symptom–sign correlation Symptoms may be disproportionate to tear dysfunction; chronicity and family history important. Symptoms usually correlate with tear-film metrics and ocular surface parameters. Disproportionate symptoms with minimal tear pathology should prompt consideration of MECD and IVCM. Although superficial examination may appear similar, MECD is defined by a distinct microstructural pathology that is absent in DED. As illustrated in Fig. 1 - 2 A–D, MECD manifests as a symmetric, bilateral grey-white epithelial haze that resolves on retroillumination into sharply demarcated intraepithelial lucencies corresponding to microcysts. In contrast, DED demonstrates generalized epithelial roughening without discrete cystic changes, with retroillumination showing only diffuse light scatter from an irregular tear film (Fig. 4 A–D). These structural differences underlie the observed staining patterns. In MECD, punctate fluorescein staining is persistent and focal, directly overlying the microcysts and reflecting a stable but dysplastic epithelial architecture (Fig. 1 – 2 ,E–F). By comparison, DED staining is superficial, diffuse, and transient, fluctuating with blink dynamics and tear film instability (Fig. 4 E–F). In vivo confocal microscopy (IVCM) provides the most definitive microstructural distinction. MECD scans reveal numerous sharply demarcated hyporeflective intraepithelial lacunae (microcysts) disrupting the normal epithelial mosaic, often containing hyperreflective debris (Fig. 1 M–P). DED scans, by contrast, show only diffuse epithelial hyperreflectivity and surface irregularity, with no evidence of discrete intraepithelial lacunae (Fig. 4 G–H). Discussion and Conclusiom This familial case emphasizes the diagnostic challenge of distinguishing MECD from refractory DED, a distinction with meaningful clinical implications. Early recognition of MECD prevents prolonged ineffective DED therapy, avoids unnecessary escalation of treatment, and facilitates informed genetic counseling and family screening 7 . While numerous MECD-associated mutations have been documented, primarily in KRT3 (type II keratin) and KRT12 (type I keratin), our report identifies a previously unreported KRT3 variant, expanding the mutational spectrum in autosomal dominant MECD 6 , 36 – 40 . Clinically, MECD can mimic DED because superficial punctate staining is superficially similar to that observed in ocular surface desiccation 41 – 43 . However, careful slit-lamp evaluation with pre-fluorescein retroillumination reveals multiple, sharply demarcated intraepithelial microcysts across the interpalpebral cornea 44 , 45 . These microcysts produce a glistening, punctate lucency against an otherwise clear stroma, often symmetrically and reproducibly across affected relatives 4 , 41 . In contrast, DED exhibits diffuse light scattering secondary to tear-film instability, with epithelial irregularities that fluctuate with blinking or environmental stress 43 . Fluorescein staining patterns provide additional discriminatory value. In MECD, staining is typically restricted to discrete areas of epithelial fragility overlying the microcysts and remains persistent across time, reflecting the underlying epithelial architecture rather than transient tear-film disruption. Notably, fluorescein rarely penetrates the cystic spaces themselves 41 . By contrast, DED-related staining fluctuates with tear metrics and environmental conditions, often appearing as diffuse punctate erosions 7 , 43 . Thus, persistent focal staining despite optimized tear parameters should prompt consideration of MECD and further imaging. IVCM reinforces this distinction. MECD demonstrates round or oval hyporeflective intraepithelial lacunae containing reflective debris, distributed throughout superficial and basal epithelial layers 46 , 47 . Superficial cystic spaces are larger and more dispersed, while basal cysts are smaller and tightly packed, consistent with histopathological reports 3 , 48 . By contrast, DED typically presents diffuse epithelial hyperreflectivity, thinning, and architectural irregularity, without discrete cystic formations 49 , 50 . Sequential scanning from superficial to basal epithelium, encompassing central and interpalpebral regions, is recommended to maximize detection of subclinical microcysts. Therefore, in patients whose symptoms are disproportionate to tear film metrics or who exhibit therapy-refractory dry eye, the detection of a bilateral, familial pattern of microcystic epithelial changes on high-magnification examination and retroillumination should prompt further evaluation. In this context, IVCM is particularly valuable for confirming the cystic epithelial phenotype, enabling differentiation of MECD from DED and guiding appropriate patient management and genetic counseling. From a therapeutic perspective, recognizing MECD early avoids ineffective long-term DED therapy. Management remains largely supportive, including lubricating drops and episodic anti-inflammatory treatment for symptomatic relief. In selected cases, phototherapeutic keratectomy or superficial keratectomy can improve epithelial smoothness, although recurrence may occur depending on lesion depth. The divergent natural histories of MECD and DED underscore the clinical relevance of accurate diagnosis: whereas DED partially responds to tear-stabilizing and anti-inflammatory measures, MECD management focuses on structural assessment and, when indicated, procedural intervention. Limitations of the present report include the single-family scope and absence of functional validation for the novel KRT3 variant. Broader familial screening, submission to ClinVar, and functional assays, such as keratin filament assembly studies, are warranted to substantiate pathogenicity. Clinically, integrating slit-lamp retroillumination, persistent fluorescein staining, epithelial-layer–specific IVCM, and targeted genetic testing offers a practical framework for evaluating patients with suspected refractory DED or atypical epithelial findings. In conclusion this case highlights MECD’s potential to masquerade as DED and underscores the value of a structured, multimodal diagnostic approach. Key differentiators include pre-fluorescein retroillumination, persistent focal fluorescein staining, and layer-specific intraepithelial microcysts on IVCM. When combined with familial genetic assessment, these measures enable early recognition, informed counseling, and avoidance of ineffective long-term therapy, thereby enhancing patient care and clinical efficiency. Abbreviations MECD: Meesmann epithelial corneal dystrophy , DED: Dry eye disease , IVCM: In vivo confocal microscopy , KRT3: Keratin 3 , bFGF: Basic fibroblast growth factor , VA: Visual acuity , ACMG: American College of Medical Genetics and Genomics , AMP: Association for Molecular Pathology , REVEL: Rare Exome Variant Ensemble Learner Declarations Acknowledgments The authors would like to thank all doctors and laboratory technicians who contributed to examining, diagnosing and treating patients. Author Contribution Ahyan Ilman Qudsi conceived and designed the study, collected and analyzed the data, interpreted the findings, and drafted the manuscript. Jinding Pang performed the imaging. Qingfeng Liang supervised the study, contributed to study design and data interpretation, critically revised the manuscript, and approved the final version. All authors have read and approved the final manuscript. Funding This research was funded by the Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (PWD&RPP-MRI, JYY2023-6); National Key Research and Development Program, grant number 2021YFC2301000. Availability of data and materials The datasets generated and/or analysed during the current study are available in the ClinVar repository, https://submit.ncbi.nlm.nih.gov/subs/clinvar_wizard/SUB16040774/overview, Submission ID: SUB16040774. Ethics approval The study adhered to the Declaration of Helsinki and received approval from the Medical Ethics Committee of Beijing Tongren Hospital (TRECKY2021–024). Consent to participate The patient granted permission to participate. Written informed consent to participate in this case-report was obtained from the patient. Consent for publication The patient granted permission to publish this information. Written informed consent for the publication of this case-report was obtained from the patient. 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Imaging the microstructural abnormalities of meesmann corneal dystrophy by in vivo confocal microscopy. Cornea. 2005;24(6):669-673. doi:10.1097/01.ico.0000154389.51125.70. Fine BS, Yanoff M, Pitts E, Slaughter FD. Meesmann’s epithelial dystrophy of the cornea. Am J Ophthalmol. 1977;83(5):633-642. doi:10.1016/0002-9394(77)90128-3. Gupta SK, Hodge WG. A new clinical perspective of corneal dystrophies through molecular genetics. Curr Opin Ophthalmol. 1999;10(4):234-241. doi:10.1097/00055735-199908000-00003. Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis . 2009;4(1):7. doi:10.1186/1750-1172-4-7 Mokhtarzadeh M, Casey R, Glasgow BJ. Fluorescein Punctate Staining Traced to Superficial Corneal Epithelial Cells by Impression Cytology and Confocal Microscopy. Investig Opthalmology Vis Sci . 2011;52(5):2127. doi:10.1167/iovs.10-6489 Thinda S, Sikh PK, Hopp LM, Glasgow BJ. Polycarbonate membrane impression cytology: evidence for fluorescein staining in normal and dry eye corneas. Br J Ophthalmol . 2010;94(4):406-409. doi:10.1136/bjo.2009.167031 Kivelä, T. T., Messmer, E. M., & Rymgayllo-Jankowska, B. (2015). Cornea. In S. Heegaard, & H. Grossniklaus (Eds.), Eye Pathology: An Illustrated Guide (1 Ed.). Article 3 Springer-Verlag. Https://Doi.Org/10.1007/978-3-662-43382-9 . Lisch, W., Janecke, A., Seitz, B. (2009). Corneal Dystrophy, Meesmann. In: Lang, F. (Eds) Encyclopedia of Molecular Mechanisms of Disease. Springer, Berlin, Heidelberg. Https://Doi.Org/10.1007/978-3-540-29676-8_3298 . Patel DV, Grupcheva CN, McGhee CNJ. Imaging the Microstructural Abnormalities of Meesmann Corneal Dystrophy by In Vivo Confocal Microscopy. 2005;24(6). Shukla AN, Cruzat A, Hamrah P. Confocal Microscopy of Corneal Dystrophies. Semin Ophthalmol . 2012;27(5-6):107-116. doi:10.3109/08820538.2012.707276 Vemuganti GK, Rathi VM, Murthy SI. Histological Landmarks in Corneal Dystrophy: Pathology of Corneal Dystrophies. In: Lisch W, Seitz B, eds. Developments in Ophthalmology . Vol 48. S. Karger AG; 2011:24-50. doi:10.1159/000324261 Kheirkhah A, Rahimi Darabad R, Cruzat A, et al. Corneal Epithelial Immune Dendritic Cell Alterations in Subtypes of Dry Eye Disease: A Pilot In Vivo Confocal Microscopic Study. Investig Opthalmology Vis Sci . 2015;56(12):7179. doi:10.1167/iovs.15-17433 Sim R, Yong K, Liu YC, Tong L. In Vivo Confocal Microscopy in Different Types of Dry Eye and Meibomian Gland Dysfunction. J Clin Med . 2022;11(9):2349. doi:10.3390/jcm11092349 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8973040","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":606526112,"identity":"d55ef2d9-b390-40d2-8c5d-18f7b215cb96","order_by":0,"name":"Ahyan Ilman Qudsi","email":"","orcid":"","institution":"Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ahyan","middleName":"Ilman","lastName":"Qudsi","suffix":""},{"id":606526121,"identity":"ded214c2-9189-4c17-88b3-8a6cdf3521e8","order_by":1,"name":"Jinding Pang","email":"","orcid":"","institution":"Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jinding","middleName":"","lastName":"Pang","suffix":""},{"id":606526124,"identity":"da6db5a7-ae3a-4ff5-82e5-599ab04e8426","order_by":2,"name":"Qingfeng Liang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIiWNgGAWjYBACPmYwJcHAwHwASFdAhXnwaGGDa2FLANJniNGCYAG1MLYRo4Wd+dnDL2UWefJuzMcefp1nJ687I4Hxwds2BnlznA5jMzeWOSdRbHiMLd1Ydluy4bYbCcyGc9sYDHc24PSLmbRkm0Tixvk9QMa2AwlmNxLYpHnbGBIMDuDSwv4NoqWNH8iYA9bC/hu/Fh4zyY9ALfPZeNgkPzZAbGEmoKVMmuGcROIGNjYzaYZjQL+cedgsOeechOEGHFr4+Y9vk/xRVpc4v435meSPGjt5s+PJBz+8KbORx2ULCDDzAGMHpIAZEh2MDQzgyMUDGH8Atcg3gBh41Y2CUTAKRsFIBQCbyVJXHANraQAAAABJRU5ErkJggg==","orcid":"","institution":"Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Qingfeng","middleName":"","lastName":"Liang","suffix":""}],"badges":[],"createdAt":"2026-02-26 04:08:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8973040/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8973040/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104878847,"identity":"3ace0c94-c465-4e67-86b5-de39607ce567","added_by":"auto","created_at":"2026-03-18 08:58:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1307651,"visible":true,"origin":"","legend":"\u003cp\u003eDiagnostic imaging of Meesmann corneal dystrophy in the proband (II-1). Panels A and B show external photographs of both eyes, C and D show retro-illumination highlighting intraepithelial microcysts, E and F show fluorescein staining demonstrating milder punctate epithelial erosions after dry eye treatment, and G and H show in vivo confocal microscopy (IVCM) revealing hyperreflective intraepithelial microcysts and epithelial cell irregularities.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8973040/v1/999c9cf359783d3359128a8f.png"},{"id":104878961,"identity":"d843edd4-51cc-4172-9a17-4fd0bd7e5e68","added_by":"auto","created_at":"2026-03-18 08:59:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1295550,"visible":true,"origin":"","legend":"\u003cp\u003eDiagnostic imaging of the proband’s son (III-1). Panels A and B show external photographs of both eyes, C and D show retro-illumination of diffuse intraepithelial microcysts, E and F show fluorescein staining of punctate epithelial erosions, and G and H show IVCM of hyperreflective intraepithelial microcysts and epithelial cell irregularities.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8973040/v1/2a4dc057ebc953adc3bf66ac.png"},{"id":104878873,"identity":"aa6ae89c-48fb-4077-8fdf-f649abf07709","added_by":"auto","created_at":"2026-03-18 08:58:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":163829,"visible":true,"origin":"","legend":"\u003cp\u003eSanger sequencing chromatograms confirm the familial segregation of the \u003cem\u003eKRT3\u003c/em\u003e variant.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8973040/v1/0e18c25e62951df7f4d561f3.png"},{"id":104878966,"identity":"2d31b292-8dff-4b4e-8764-cbba34dd7e9f","added_by":"auto","created_at":"2026-03-18 08:59:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1155827,"visible":true,"origin":"","legend":"\u003cp\u003eDistinctive microstructural features of dry eye disease (DED) compared with Meesmann corneal dystrophy (MECD). Panels A and B show external photographs of representative DED eyes, C and D show retro-illumination highlighting diffuse epithelial irregularity without discrete microcysts, E and F show fluorescein staining demonstrating superficial, transient punctate epithelial erosions, and G and H show in vivo confocal microscopy (IVCM) revealing diffuse epithelial hyperreflectivity without intraepithelial lacunae or cysts.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8973040/v1/bb428c56a5eef236efefcfbc.png"},{"id":104967834,"identity":"4c789111-0658-4a81-b087-5794711de53a","added_by":"auto","created_at":"2026-03-19 10:12:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5700062,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8973040/v1/aaa27545-da7e-4157-bf4b-b1142614b5d1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Meesmann Corneal Dystrophy Misdiagnosed as Refractory Dry Eye Disease: A case Report","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMeesmann epithelial corneal dystrophy (MECD) is a rare autosomal-dominant disorder of the corneal epithelium, marked by numerous punctate intraepithelial microcysts predominantly across the interpalpebral region \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Histopathological examination reveals epithelial vacuoles containing aberrant keratin aggregates, reflecting disrupted intermediate filament assembly within suprabasal epithelial cells. Clinical manifestations typically begin in early life, yet symptom severity is highly variable, ranging from mild ocular irritation to photophobia and transient visual blur \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Within families, incomplete penetrance and pronounced variability in expressivity are frequently observed \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBecause early MECD changes can be subtle under routine diffuse illumination, affected individuals are occasionally misdiagnosed with severe dry eye disease (DED) or nonspecific epithelial keratopathy, delaying definitive diagnosis and appropriate genetic counseling \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. In this context, pre-fluorescein retroillumination, epithelial-layer in vivo confocal microscopy (IVCM), and targeted genetic sequencing substantially enhance diagnostic specificity \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. We describe a Chinese pedigree, initially managed as refractory DED, in which retroillumination and IVCM revealed a characteristic MECD microcystic phenotype. Genetic analysis identified a previously unreported heterozygous KRT3 missense variant, c.1525G\u0026thinsp;\u0026gt;\u0026thinsp;C, p.(Glu509Gln), affecting a residue recurrently implicated in MECD. We further discuss practical clinical discriminators and variant interpretation considerations within the broader spectrum of known KRT3 and KRT12 mutations.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eClinical Findings\u003c/h2\u003e\n \u003cp\u003e55-year-old Chinese man with a ten-year history of well-controlled type 2 diabetes who presented on 17 June 2025 with a six-month history of bilateral ocular discomfort, including dryness, intermittent foreign-body sensation, and progressive visual blur. At presentation, uncorrected visual acuity was 0.03 in the right eye and 0.3 in the left eye. Slit-lamp examination revealed a narrow tear meniscus, mild bulbar hyperemia, and diffuse punctate epithelial erosions in both eyes. No focal epithelial opacities, subepithelial changes, or stromal abnormalities were observed at that stage.\u003c/p\u003e\n \u003cp\u003eBased on the presenting symptoms and diffuse punctate epithelial staining, provisional diagnoses included conjunctivitis, dry eye disease, and age-related cataract. Initial therapy comprised topical gatifloxacin gel, 0.02% fluorometholone, recombinant bovine basic fibroblast growth factor, vitamin A palmitate gel, and 0.2% cyclosporine. Medication regimens were adjusted according to the patient\u0026rsquo;s clinical response at subsequent visits. A summary of findings across all follow-up visits, including symptom progression, slit-lamp features, and epithelial staining, is provided in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSummary of Serial Clinical Visits Prior to Definitive Diagnosis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKey Clinical Findings\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eProvisional Diagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eManagement\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJune 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNarrow tear meniscus; mild conjunctival injection; diffuse punctate epithelial staining\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConjunctivitis / Dry eye / Cataract\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSodium hyaluronate, cyclosporine, bFGF, vit A gel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJul 22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMeibomian gland plugs; persistent epithelial staining\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKeratitis / Dry eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFluorometholone, levofloxacin, vit A gel\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAug 26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimilar exam; no improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKeratitis / Dry eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eContinued topical therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSep 23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePersistent epithelial irregularity, stroma clear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBilateral epithelial keratopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eObservation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOct 21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntraepithelial microcysts detected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuspected epithelial dystrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIVCM and Genetic testing initiated including the son\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eOver the subsequent months, the patient remained compliant with the prescribed therapy but reported no meaningful subjective improvement. Serial examinations demonstrated persistent punctate epithelial changes accompanied by stable tear-film abnormalities, and obstruction of several meibomian gland orifices was newly identified. Punctate staining continued to worsen, most prominently in the right eye, despite three months of uninterrupted treatment. With intensified lubrication, the staining showed modest reduction; however, the overall epithelial appearance remained consistent with a typical dry eye pattern. The discrepancy between symptoms, treatment duration, and the partial, inconsistent surface response raised concern that the initial diagnoses did not fully explain the underlying disease process.\u003c/p\u003e\n \u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Diagnostic imaging of Meesmann corneal dystrophy in the proband (II-1). Panels A and B show external photographs of both eyes, C and D show retro-illumination highlighting intraepithelial microcysts, E and F show fluorescein staining demonstrating milder punctate epithelial erosions after dry eye treatment, and G and H show in vivo confocal microscopy (IVCM) revealing hyperreflective intraepithelial microcysts and epithelial cell irregularities.\u003c/p\u003e\n \u003cp\u003eA focused re-evaluation was performed four months after the initial visit. Retroillumination prior to fluorescein instillation revealed numerous small, glistening intraepithelial microcysts scattered across the interpalpebral zone of both corneas (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eC-D). These lesions had not been detected during earlier examinations. Fluorescein staining was now minimal, suggesting that lubrication had smoothed the surface without addressing the underlying epithelial disruption. The observed microcyst pattern strongly suggested a hereditary epithelial abnormality, and MECD emerged as the leading consideration in the differential diagnosis.\u003c/p\u003e\n \u003cp\u003eGiven the emerging suspicion of a hereditary epithelial disorder, a structural assessment using IVCM was performed. The scans revealed a dense population of round and oval hyperreflective intraepithelial microcysts in both eyes, involving the superficial and basal epithelial layers. Smaller, tightly arranged microcysts predominated in the basal epithelium, while the superficial layer contained larger cystic spaces interspersed with hyperreflective cellular debris. This distribution and morphology correspond closely with the epithelial architecture reported in MECD. Representative images are shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eG-H.\u003c/p\u003e\n \u003cp\u003eBecause the clinical findings suggested an inherited epithelial disorder, first-degree relatives were evaluated. The only available family member, the proband\u0026rsquo;s thirty-year-old son (III-1), who accompanied him to the clinic, underwent a comprehensive ophthalmic assessment. No additional relatives could be examined, as the proband\u0026rsquo;s father and paternal grandfather were deceased. Although asymptomatic, the son demonstrated numerous, uniform microcysts on retroillumination and denser, more tightly clustered microcysts on in vivo confocal microscopy compared with his father (II-1) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC\u0026ndash;D). Fluorescein staining revealed more pronounced punctate epithelial erosions than in his father (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC-F), likely reflecting the absence of prior dry eye therapy, while his IVCM findings were typical and closely mirrored those observed in his father (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eG-H). Collectively, these observations underscore the bilateral, familial pattern of microcystic epithelial changes and support the inherited nature of the disorder.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eGenetic Findings\u003c/h3\u003e\n\u003cp\u003eTargeted next-generation sequencing using a corneal dystrophy panel identified a heterozygous KRT3 c.1525G\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Glu509Gln) variant in both affected individuals. Sanger sequencing confirmed the heterozygous substitution in the proband (II-1) and his son (III-1), consistent with familial segregation (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Electropherograms displayed clear dual peaks (G/C) at the variant position, providing molecular evidence of co-segregation with the phenotype across two affected generations. The variant has not been previously reported in ClinVar or other publicly available databases and is absent from population datasets (gnomAD, ExAC). In silico analysis (REVEL\u0026thinsp;=\u0026thinsp;0.82) predicts the variant to be deleterious. According to ACMG guidelines, it is currently classified as a Variant of Uncertain Significance (VUS), with supporting evidence including absence from population databases, computational predictions, and segregation with disease in the family. Notably, prior studies have repeatedly implicated substitutions at Glu509 within exon 7 of KRT3 as recurrent hotspots for MECD, including p.Glu509Lys and p.Glu509Asp, each associated with the classic microcystic epithelial phenotype. The involvement of the same residue suggests that additional evidence may justify reclassification of p.Glu509Gln to likely pathogenic in future updates.\u003c/p\u003e\n\u003cp\u003eTo contextualize, prior reports have identified seven distinct KRT3 variants and twenty-five KRT12 variants associated with Meesmann corneal dystrophy, with several studies highlighting substitutions at Glu509 in exon 7 of KRT3 (e.g., p.Glu509Lys, p.Glu509Asp) as recurrent hotspots linked to the classic microcystic epithelial phenotype \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. The involvement of the same residue suggests that additional evidence may justify reclassifying p.Glu509Gln as likely pathogenic in future updates. Although formally classified as a variant of uncertain significance under ACMG/AMP guidelines, the cumulative evidence supports a likely pathogenic interpretation \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. This assessment is based on its absence from population databases, a deleterious computational score (REVEL\u0026thinsp;=\u0026thinsp;0.82), segregation across two affected family members, and close phenotypic concordance with previously reported MECD presentations \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eDiagnostic Considerations\u003c/h3\u003e\n\u003cp\u003eThe clinical presentation of MECD can closely resemble common ocular surface disorders, particularly dry eye disease (DED), which may lead to delayed or misdirected diagnosis. To clarify this overlap and identify key distinguishing features, we systematically compared multimodal imaging from our cohort of genetically confirmed MECD cases (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e) with imaging from clinically representative DED patient (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). The distinguishing clinical and microstructural characteristics are summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eKey distinguishing features of MECD versus DED: clinical, staining, and microstructural correlates\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFeature\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMECD findings\u003c/p\u003e\n \u003cp\u003e(clinical / imaging)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDED findings\u003c/p\u003e\n \u003cp\u003e(clinical / imaging)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDiagnostic significance\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiffuse slit-lamp (white-light)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubtle grey-white epithelial haze with focal surface irregularity and punctate microcystic changes; often symmetric and seen across affected family members. Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e,2.\u003cstrong\u003eA-D\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGeneralized epithelial roughening and granular surface irregularity without discrete microcysts; variable and often asymmetric. Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003cstrong\u003eA-B\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePresence of a bilateral, consistent microcystic haze across relatives favors MECD over DED.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRetro-illumination\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSharply demarcated, punctate areas of altered translucency corresponding to intraepithelial microcysts; discrete lucencies stand out against otherwise clear stroma. Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e,2.\u003cstrong\u003eE-H\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiffuse light-scattering from tear-film breakup and surface desiccation; lacks discrete cystic lucencies. Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003cstrong\u003eC-D\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRetro-illumination that reveals sharply circumscribed intraepithelial lucencies is highly suggestive of MECD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFluorescein / vital-dye staining pattern\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePunctate staining that localizes to discrete areas of epithelial fragility overlying microcysts; staining is persistent and focal, reflecting underlying architecture. Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e,2.\u003cstrong\u003eI-L\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuperficial, diffuse punctate erosions that fluctuate with blink and tear-film stability; more transient. Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003cstrong\u003eE-F\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePersistent, focal staining despite normal/near-normal tear metrics suggests structural epithelial disease (MECD) rather than purely tear-film instability.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTemporal dynamics of staining\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePersistent, reproducible pattern over time and visits; does not markedly change with blink/tear-film manipulation.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVariable; staining distribution changes with blink, environmental conditions and tear metrics.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLack of fluctuation with blink/tear interventions supports MECD.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eIn vivo confocal microscopy (IVCM)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumerous sharply demarcated hyporeflective intraepithelial lacunae (microcysts) within a disrupted epithelial mosaic; lacunae may contain reflective debris and are bounded by irregular cell borders. Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e,2.\u003cstrong\u003eM-P\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiffuse epithelial hyperreflectivity and irregular superficial architecture without discrete intraepithelial lacunae/cysts. Figure \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003cstrong\u003eG-H\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIVCM provides the most specific microstructural discriminator: discrete lacunae\u0026thinsp;=\u0026thinsp;MECD; diffuse hyperreflectivity without lacunae\u0026thinsp;=\u0026thinsp;DED.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSymptom\u0026ndash;sign correlation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSymptoms may be disproportionate to tear dysfunction; chronicity and family history important.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSymptoms usually correlate with tear-film metrics and ocular surface parameters.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisproportionate symptoms with minimal tear pathology should prompt consideration of MECD and IVCM.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAlthough superficial examination may appear similar, MECD is defined by a distinct microstructural pathology that is absent in DED. As illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e-\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA\u0026ndash;D, MECD manifests as a symmetric, bilateral grey-white epithelial haze that resolves on retroillumination into sharply demarcated intraepithelial lucencies corresponding to microcysts. In contrast, DED demonstrates generalized epithelial roughening without discrete cystic changes, with retroillumination showing only diffuse light scatter from an irregular tear film (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA\u0026ndash;D).\u003c/p\u003e\n\u003cp\u003eThese structural differences underlie the observed staining patterns. In MECD, punctate fluorescein staining is persistent and focal, directly overlying the microcysts and reflecting a stable but dysplastic epithelial architecture (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e,E\u0026ndash;F). By comparison, DED staining is superficial, diffuse, and transient, fluctuating with blink dynamics and tear film instability (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eE\u0026ndash;F).\u003c/p\u003e\n\u003cp\u003eIn vivo confocal microscopy (IVCM) provides the most definitive microstructural distinction. MECD scans reveal numerous sharply demarcated hyporeflective intraepithelial lacunae (microcysts) disrupting the normal epithelial mosaic, often containing hyperreflective debris (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eM\u0026ndash;P). DED scans, by contrast, show only diffuse epithelial hyperreflectivity and surface irregularity, with no evidence of discrete intraepithelial lacunae (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eG\u0026ndash;H).\u003c/p\u003e"},{"header":"Discussion and Conclusiom","content":"\u003cp\u003eThis familial case emphasizes the diagnostic challenge of distinguishing MECD from refractory DED, a distinction with meaningful clinical implications. Early recognition of MECD prevents prolonged ineffective DED therapy, avoids unnecessary escalation of treatment, and facilitates informed genetic counseling and family screening \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. While numerous MECD-associated mutations have been documented, primarily in KRT3 (type II keratin) and KRT12 (type I keratin), our report identifies a previously unreported KRT3 variant, expanding the mutational spectrum in autosomal dominant MECD \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan additionalcitationids=\"CR37 CR38 CR39\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eClinically, MECD can mimic DED because superficial punctate staining is superficially similar to that observed in ocular surface desiccation \u003csup\u003e\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. However, careful slit-lamp evaluation with pre-fluorescein retroillumination reveals multiple, sharply demarcated intraepithelial microcysts across the interpalpebral cornea \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. These microcysts produce a glistening, punctate lucency against an otherwise clear stroma, often symmetrically and reproducibly across affected relatives \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. In contrast, DED exhibits diffuse light scattering secondary to tear-film instability, with epithelial irregularities that fluctuate with blinking or environmental stress \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFluorescein staining patterns provide additional discriminatory value. In MECD, staining is typically restricted to discrete areas of epithelial fragility overlying the microcysts and remains persistent across time, reflecting the underlying epithelial architecture rather than transient tear-film disruption. Notably, fluorescein rarely penetrates the cystic spaces themselves \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. By contrast, DED-related staining fluctuates with tear metrics and environmental conditions, often appearing as diffuse punctate erosions \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Thus, persistent focal staining despite optimized tear parameters should prompt consideration of MECD and further imaging.\u003c/p\u003e \u003cp\u003eIVCM reinforces this distinction. MECD demonstrates round or oval hyporeflective intraepithelial lacunae containing reflective debris, distributed throughout superficial and basal epithelial layers \u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Superficial cystic spaces are larger and more dispersed, while basal cysts are smaller and tightly packed, consistent with histopathological reports \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e. By contrast, DED typically presents diffuse epithelial hyperreflectivity, thinning, and architectural irregularity, without discrete cystic formations \u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e,\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. Sequential scanning from superficial to basal epithelium, encompassing central and interpalpebral regions, is recommended to maximize detection of subclinical microcysts.\u003c/p\u003e \u003cp\u003eTherefore, in patients whose symptoms are disproportionate to tear film metrics or who exhibit therapy-refractory dry eye, the detection of a bilateral, familial pattern of microcystic epithelial changes on high-magnification examination and retroillumination should prompt further evaluation. In this context, IVCM is particularly valuable for confirming the cystic epithelial phenotype, enabling differentiation of MECD from DED and guiding appropriate patient management and genetic counseling.\u003c/p\u003e \u003cp\u003eFrom a therapeutic perspective, recognizing MECD early avoids ineffective long-term DED therapy. Management remains largely supportive, including lubricating drops and episodic anti-inflammatory treatment for symptomatic relief. In selected cases, phototherapeutic keratectomy or superficial keratectomy can improve epithelial smoothness, although recurrence may occur depending on lesion depth. The divergent natural histories of MECD and DED underscore the clinical relevance of accurate diagnosis: whereas DED partially responds to tear-stabilizing and anti-inflammatory measures, MECD management focuses on structural assessment and, when indicated, procedural intervention.\u003c/p\u003e \u003cp\u003eLimitations of the present report include the single-family scope and absence of functional validation for the novel KRT3 variant. Broader familial screening, submission to ClinVar, and functional assays, such as keratin filament assembly studies, are warranted to substantiate pathogenicity. Clinically, integrating slit-lamp retroillumination, persistent fluorescein staining, epithelial-layer\u0026ndash;specific IVCM, and targeted genetic testing offers a practical framework for evaluating patients with suspected refractory DED or atypical epithelial findings.\u003c/p\u003e \u003cp\u003eIn conclusion this case highlights MECD\u0026rsquo;s potential to masquerade as DED and underscores the value of a structured, multimodal diagnostic approach. Key differentiators include pre-fluorescein retroillumination, persistent focal fluorescein staining, and layer-specific intraepithelial microcysts on IVCM. When combined with familial genetic assessment, these measures enable early recognition, informed counseling, and avoidance of ineffective long-term therapy, thereby enhancing patient care and clinical efficiency.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eMECD:\u0026nbsp;\u003c/strong\u003eMeesmann epithelial corneal dystrophy\u003cstrong\u003e, DED:\u0026nbsp;\u003c/strong\u003eDry eye disease\u003cstrong\u003e, IVCM:\u0026nbsp;\u003c/strong\u003eIn vivo confocal microscopy\u003cstrong\u003e, KRT3:\u0026nbsp;\u003c/strong\u003eKeratin 3\u003cstrong\u003e, bFGF:\u0026nbsp;\u003c/strong\u003eBasic fibroblast growth factor\u003cstrong\u003e, VA:\u0026nbsp;\u003c/strong\u003eVisual acuity\u003cstrong\u003e, ACMG:\u0026nbsp;\u003c/strong\u003eAmerican College of Medical Genetics and Genomics\u003cstrong\u003e, AMP:\u0026nbsp;\u003c/strong\u003eAssociation for Molecular Pathology\u003cstrong\u003e, REVEL:\u0026nbsp;\u003c/strong\u003eRare Exome Variant Ensemble Learner\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all doctors and laboratory technicians who contributed to examining, diagnosing and treating patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAhyan Ilman Qudsi conceived and designed the study, collected and analyzed the data, interpreted the findings, and drafted the manuscript. Jinding Pang performed the imaging. Qingfeng Liang supervised the study, contributed to study design and data interpretation, critically revised the manuscript, and approved the final version. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by the Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (PWD\u0026amp;RPP-MRI, JYY2023-6); National Key Research and Development Program, grant number 2021YFC2301000.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available in the ClinVar repository, https://submit.ncbi.nlm.nih.gov/subs/clinvar_wizard/SUB16040774/overview, Submission ID: SUB16040774.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study adhered to the Declaration of Helsinki and received approval from the Medical Ethics Committee of Beijing Tongren Hospital (TRECKY2021\u0026ndash;024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient granted permission to participate. Written informed consent to participate in this case-report was obtained from the patient.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient granted permission to publish this information. Written informed consent for the publication of this case-report was obtained from the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWeiss JS, M\u0026oslash;ller HU, Aldave AJ, et al. IC3D Classification of Corneal Dystrophies\u0026mdash;Edition 2. 2015;34(2).\u003c/li\u003e\n\u003cli\u003eSoh YQ, Kocaba V, Weiss JS, et al. 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Histological Landmarks in Corneal Dystrophy: Pathology of Corneal Dystrophies. In: Lisch W, Seitz B, eds. \u003cem\u003eDevelopments in Ophthalmology\u003c/em\u003e. Vol 48. S. Karger AG; 2011:24-50. doi:10.1159/000324261\u003c/li\u003e\n\u003cli\u003eKheirkhah A, Rahimi Darabad R, Cruzat A, et al. Corneal Epithelial Immune Dendritic Cell Alterations in Subtypes of Dry Eye Disease: A Pilot In Vivo Confocal Microscopic Study. \u003cem\u003eInvestig Opthalmology Vis Sci\u003c/em\u003e. 2015;56(12):7179. doi:10.1167/iovs.15-17433\u003c/li\u003e\n\u003cli\u003eSim R, Yong K, Liu YC, Tong L. In Vivo Confocal Microscopy in Different Types of Dry Eye and Meibomian Gland Dysfunction. \u003cem\u003eJ Clin Med\u003c/em\u003e. 2022;11(9):2349. doi:10.3390/jcm11092349\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":"Corneal dystrophy, Meesmann dystrophy, KRT3, gene mutation, Diagnosis","lastPublishedDoi":"10.21203/rs.3.rs-8973040/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8973040/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMeesmann epithelial corneal dystrophy (MECD) is a well-recognized autosomal-dominant epithelial disorder caused by keratin mutations and classically characterized by diffuse intraepithelial microcysts. However, when these microcysts are subtle on routine slit-lamp examination, the condition may closely mimic chronic dry eye disease, leading to delayed diagnosis and prolonged ineffective therapy. We report a familial case initially managed as refractory dry eye disease in which multimodal imaging and genetic analysis established the correct diagnosis and identified a previously unreported keratin 3 variant.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e \u003cp\u003eA 55-year-old Chinese man with well-controlled type 2 diabetes presented with six months of bilateral ocular discomfort and progressive visual blur. Slit-lamp examination demonstrated a narrow tear meniscus and diffuse punctate epithelial erosions without obvious dystrophic features, and he was treated for presumed dry eye disease with lubricants, anti-inflammatory agents, and epithelial trophic therapy over several months without meaningful improvement. The persistence of epithelial irregularity despite therapy prompted re-evaluation, and pre-fluorescein retroillumination revealed numerous glistening intraepithelial microcysts across the interpalpebral cornea. In vivo confocal microscopy confirmed dense, sharply demarcated microcysts involving superficial and basal epithelial layers. Examination of his asymptomatic 30-year-old son disclosed similar bilateral microcystic changes. Targeted next-generation sequencing identified a heterozygous keratin 3 missense variant (c.1525G\u0026thinsp;\u0026gt;\u0026thinsp;C, p.Glu509Gln) in both individuals, with Sanger sequencing confirming familial segregation. The variant is absent from population databases and predicted to be deleterious by computational analysis, supporting the diagnosis of Meesmann epithelial corneal dystrophy.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMECD may masquerade as therapy-refractory dry eye disease when microcysts are inconspicuous on standard examination. Persistent epithelial changes despite optimized tear management should prompt retroillumination, in vivo confocal microscopy, and consideration of genetic testing. Early recognition prevents prolonged misdirected treatment and enables appropriate family counseling.\u003c/p\u003e","manuscriptTitle":"Meesmann Corneal Dystrophy Misdiagnosed as Refractory Dry Eye Disease: A case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-18 08:57:29","doi":"10.21203/rs.3.rs-8973040/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":"956e707d-20fe-4ba4-99fc-2104d58d4665","owner":[],"postedDate":"March 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-19T10:11:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-18 08:57:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8973040","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8973040","identity":"rs-8973040","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}