Axenfeld-Rieger syndrome：A novel histopathologic finding associated with corneal abnormalities

Axenfeld-Rieger syndrome：A novel histopathologic finding associated with corneal abnormalities | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Axenfeld-Rieger syndrome：A novel histopathologic finding associated with corneal abnormalities Ting Yu, Zhihao Dai, Rongmei Peng, Gege Xiao, Pei Zhang, Siyi Ma, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1681755/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Dec, 2022 Read the published version in BMC Ophthalmology → Version 1 posted 12 You are reading this latest preprint version Abstract Background: Axenfeld-Rieger syndrome (ARS) is a rare kind of anterior segment dysgenesis (ASD). The most common ocular features of ARS are posterior embryotoxon and iris hypoplasia, while some patients may manifest as corneal opacity and edema. However, the current understanding of how ARS affects the cornea is still incomplete. This study reports a novel histopathological finding of Axenfeld-Rieger syndrome (ARS), complicating corneal abnormalities, including congenital corneal opacity and irreversible endothelial decompensation. Methods: This retrospective study included 6 eyes of 3 ARS patients who underwent keratoplasty for irreversible endothelial decompensation from May 2016 to January 2019. No eye had a history of surgery or glaucoma. We reviewed the data of epidemiology, clinical manifestations and pathological examinations. Results: Five eyes developed irreversible endothelial decompensation, among which 4 were born with corneal opacity. One eye exhibited transparent cornea but showed a continuous loss of endothelial cells in the absence of surgery and glaucoma thereafter. Anterior segment optical coherence tomography photographs showed that anterior synechia existed in the area with corneal opacities, where we found the interlayer splitting of the Descemet membrane inserted by hypoplastic iris and a basement membrane-like structure under a light microscope. Conclusions: Anterior synechia might be associated with corneal abnormalities in ARS patients. The novel histopathologic finding revealed the internal relation between anterior segment dysgenesis and would help explore the inner mechanism of corneal abnormalities in ARS. Axenfeld-Rieger syndrome histopathologic congenital corneal opacity endothelial decompensation Figures Figure 1 Figure 2 Introduction Axenfeld-Rieger syndrome (ARS) is a rare kind of anterior segment dysgenesis (ASD) with an estimated prevalence of 1 in 50,000 to 100,000 newborn babies [ 1 ]. The main pathogenesis of ARS is abnormal migration and differentiation of neural crest cells (NCCs) during the embryonic period, leading to multiple phenotypes of ARS [ 2 ]. The most common ocular features of ARS are posterior embryotoxon (caused by anteriorly displaced Schwalbe’s line) and iris hypoplasia (especially corectopia and polycoria). Moreover, patients may have accompanying systemic defects, including mild midface abnormalities, redundant umbilical skin, dental and cardiovascular abnormalities [ 3 ]. Corneal abnormalities, such as corneal opacity and edema, are considered the atypical features of ARS, which are caused by glaucoma or intraocular surgery in most reported cases [ 4 – 8 ]. Congenital corneal opacity (CCO) is rarely observed in ARS, while the exact mechanism remains unknown [ 9 – 11 ]. A study reported that CCO had been seen in ARS and other ASD (especially Peters anomaly) could stem from a similar underlying mechanism [ 12 ]. Besides, some patients with unexplained corneal endothelial abnormalities have been reported, but all of them were adults [ 12 – 14 ]. It is challenging to explore the real cause of those abnormalities. Therefore, our current understanding of how ARS may affect the cornea is incomplete. The characteristic histopathologic features of ARS are prominent, anteriorly displaced Schwalbe’s line and tissue strands connecting peripheral iris and corneal limbus. Moreover, it was observed that the abnormal Schwalbe’s line was composed of dense collagen and ground substance covered by a layer that resembled the Descemet membrane (DM) [ 13 ]. However, due to the small number of patients, there are lack histopathological observations focusing on the corneal opacity that primarily occurs in ARS. In this study, we analyzed 3 cases (6 eyes) of ARS with various degrees of corneal abnormalities. After keratoplasty, we performed a histopathological examination on corneal tissues and presented a new finding, which might improve our understanding of this disease. Materials And Methods Three patients (6 eyes) diagnosed with ARS complicating corneal opacity were retrospectively reviewed. All patients had undergone keratoplasty(penetrating keratoplasty, PK or Descemet stripping automated endothelial keratoplasty, DSAEK)unilaterally or bilaterally for irreversible endothelial decompensation at Peking University Third Hospital from May 2016 to January 2019. Besides, they had no surgical history or glaucoma prior to keratoplasty, which allowed us to observe the primary ocular appearance. The study was conducted following the revised Declaration of Helsinki. Ethics approval was obtained from the Institutional Review Board of Peking University Third Hospital. Informed consent was obtained from their guardians. Patients were diagnosed with ARS if either of the following characteristics were observed in either eye [ 3 , 15 ]: (1) Iris hypoplasia including loss of iris stroma, polycoria, corectopia and ectropion uveae; (2) An appearance of posterior embryotoxon under slit-lamp examination in combination with peripheral anterior synechia. Systemic features such as midface dysmorphism, dental abnormality, and redundant periumbilical skin helped diagnose ARS. The data gathered concerning demographics (age at operation, gender), family histories, systemic abnormalities, preoperative and intraoperative data, including best-corrected visual acuity (BCVA) (logMAR), intraocular pressure (IOP) (Goldmann tonometer), slit-lamp biomicroscopy findings, anterior segment optical coherence tomography (AS-OCT, Visante, Carl Zeiss Meditec, Dublin, CA, USA) photographs. Gene sequencing was recommended for all patients, yet none of them were tested. Histopathology of surgical specimens Cornea tissue (full-thickness cornea or endothelium/DM) of these patients underwent histopathological examination after surgery. Histopathologic procedures, including hematoxylin and eosin (H&E) stain and periodic acid-Schiff (PAS) stain were performed to obtain the pathologic features of the cornea sections. All the sections were examined using light microscopy. Results 4 eyes of 2 males and 2 eyes of a female were included in our study. The mean age at operation was 7.0 ± 0.43 years (ranged 6.3–7.6 years). They were clinically diagnosed as ARS and showed characteristic systemic abnormalities, while none had a family history of ocular diseases. Two patients (Patient 1 and 3) were born with corneal opacity bilaterally. Except for the left eye of Patient 2, all eyes had developed irreversible endothelial decompensation. 3 eyes (Patient 1 bilateral eyes, OU, Patient 2 right eye, OD) were treated by PK, while 2 eyes (Patient 3 OU) underwent DSAEK. Among 5 eyes that developed irreversible endothelial decompensation, BCVA ranged from 0.9 to 0.2 before the occurrence of corneal edema and declined to a range of hand motions to 1.7 afterwards. Before the operation, all the eyes maintained normal intraocular pressure without medications. Clinical observation All eyes showed iris abnormalities under a slit lamp microscope, including corectopia, polycoria, and stromal hypoplasia. Ectropion uveae was observed in the left eye of Patient 2. Both eyes of Patient 3 and the left eye of Patient 2 exhibited characteristic posterior embryotoxon, which was absent in Patient 1 (Fig. 1 ). Except for the left eye of Patient 2, corneas of all eyes presented with various degrees of edema. AS-OCT photographs of all eyes showed the peripheral anterior synechia, while in both eyes of 2 patients (Patient 1 and 3) the iris adhered to the quadrants where corneal opacities occurred (Fig. 1 ). All these eyes showed marked shallow anterior chamber and thickened cornea. Besides, an obscure interface could be seen on AS-OCT images of the right eye of Patient 2, indicating the mild detachment of DM. Confocal imaging was performed on the left eye of Patient 2. We observed endothelial cells with a normal hexagonal pattern but indistinct boundary and no primary endothelial lesion. Meanwhile, the average cell density was 2303 cell/mm 2 . The average cell density continuously declined to 1309 cell/mm 2 during a two-year follow-up period. Furthermore, the cornea remained transparent at the most recent clinic follow-up, and the eye did not develop glaucoma with regular use of topical ocular hypotensive medications. Histopathological findings H&E and PAS stained sections of 5 eyes that underwent keratoplasty and were observed under a light microscope. The endothelium/DM specimen removed from both eyes of Patient 3 after DSAEK showed an uneven thickness of DM and an absence of endothelium. We noted an anomalous structure in 3 eyes treated by PK (Patient 1 OU, Patient 2 OD). The structure was observed in the opaque area of both eyes of Patient 1 and the adherent area of the right eye of Patient 2 (Fig. 1 ). At high magnification, we found that the DMs of these 3 eyes were split and inserted by hypoplastic iris and a basement membrane-like structure (Fig. 2 ). Besides, we observed the detachment of the DM in the right eye of Patient 2 (Fig. 1 ). Discussion In this study, we retrospectively studied 3 cases of ARS together with corneal abnormalities. The patients in our study had not developed glaucoma or had a history of intraocular surgery. We hoped to observe the keratopathy and histopathological changes directly caused by ARS to deepen our understanding of this disease. During embryonic development, the NCCs and mesoderm cells migrate to the area between the surface ectoderm and the optic cup, contributing to the corneal stroma and endothelium, the iris stroma and the trabecular meshwork [ 16 ]. The development process of the posterior cornea and the iris are closely related, and the abnormalities in these processes can lead to corneal opacity and anterior synechia. A previous study on congenital corneal opacity found that the severity of the corneal opacity was positively correlated with the amount of iridocorneal adhesions [ 17 ]. In our study, the opaque areas corresponded to the adherent areas, indicating a closer relationship between these two signs. It can be speculated that in some ARS patients, the adherence of iris may occur along with the corneal abnormalities during the embryonic period. We made a novel histopathological finding which had never been reported before in ARS. In the eyes treated by PK, we observed the interlayer splitting of the DM with hypoplastic iris and a uniform, homogeneous, lightly stained basement membrane-like structure inserted in it. Besides, this feature happened to be in the area with corneal opacity and anterior synechia. Meanwhile, Ni et al. [ 18 ] had made an analogous histopathological finding in a child diagnosed with Peters anomaly, which is caused by abnormal migration and differentiation of ocular NC cells. They observed the “multiple-layer” structures at the peripheral part of the DM, with pigmented tissues inside the layers. The highly similar histopathological appearance suggests the common underlying mechanism. Currently, it is commonly believed that three waves of cell migration produce anterior segment structures. Different waves of cells formed the corneal endothelium, the corneal stroma and the iris stroma, but these processes were under control of the same transcription factors and signaling pathways [ 16 ]. Accordingly, we speculated that the NCCs might migrate to the wrong location in these patients, leading to the mixture of hypoplasia iris and the DM. After that, the abnormal development of the NCCs caused the corneal opacities and anterior synechia at these sites. However, establishing the anterior ocular segment is a complicated process affected by multiple factors [ 19 ], and a complete understanding of this process remains elusive. Further studies are needed to illustrate the specific mechanism. Furthermore, we did not find the abnormal structure in the patient treated by DSAEK, where the procedures are more likely to ruin the primary structure of the posterior cornea and less likely to cover the abnormal area. Besides, this abnormal histopathologic feature may not appear in all ARS patients complicating corneal abnormalities. Five eyes without the prior ocular disease (except ARS) or surgical history developed irreversible endothelial decompensation in our study. Endothelial decompensation had been found in several cases with ARS [ 8 , 13 , 20 ]. However, in these cases, the damage to endothelial membrane could be explained by surgery or long-standing glaucoma. Besides, corneal guttae and beaten metal appearance of corneal endothelium were observed in several cases of ARS [ 12 – 14 , 20 ]; however, it is still unclear whether this endothelial appearance is related to endothelial decompensation. We examined the endothelial cells in the left eye of Patient 2, and recorded the subsequent changes over the following two years. The result showed the cells with a normal hexagonal pattern but obscure boundary. Besides, neither corneal guttae nor the beaten metal appearance of the corneal endothelium was observed. The continuous decline in the cell count might suggest the existing damage despite the transparent cornea. This slight but progressive endothelial damage may exist in other ARS patients, yet existing theories could not explain it. It is also hard to determine whether it primarily occurred or is the result of a progression of the disease. The tissue strands extending from the edge of the corneal endothelium to peripheral iris are a major characteristic of ARS [ 13 ]. Accordingly, we hypothesized that traction of these tissue strands might cause irreversible corneal decompensation in these eyes. These tissue strands moved with the pupil and gradually lost corneal endothelial cells near the adhesion area. The surrounding endothelial cells were filled in afterwards. We found no analogous assumption in previous studies, and more research is needed to verify our opinion. Additionally, the histopathologic examination found the DMD in the right eye of Patient 2, who exhibited diffuse edema. The AS-OCT images before operation showed a weak adhesion between DM and posterior corneal stroma. DMD had been reported after penetrating keratoplasty (PK), especially in those with preexisting endothelial diseases [ 21 ]. Therefore, the operation procedures, pre-existing endothelial damage, and tissue strands' long-standing traction might jointly lead to the DMD we observed. Conclusions In conclusion, 6 eyes with ARS were specifically described in our study. We focused on congenital corneal opacity and irreversible endothelial decompensation in these eyes and explored the underlying mechanism through histopathologic examination. Consequently, we made a novel histopathologic finding and found progressive endothelial damage in 1 patient. Our results may enhance the understanding of ARS and improve the prognosis of the patients with ARS complicating corneal abnormalities. Abbreviations ARS: Axenfeld-Rieger syndrome; ASD: Anterior segment dysgenesis; NCCs: Neural crest cells; CCO: Congenital corneal opacity; DM: Descemet membrane; PK: Penetrating keratoplasty; DSAEK: Descemet stripping automated endothelial keratoplasty; BCVA: Best-corrected visual acuity; IOP: Intraocular pressure; AS-OCT: Anterior segment optical coherence tomography; H&E: Hematoxylin and eosin; PAS: Periodic acid-Schiff ; OU: bilateral eyes; OD: right eye; OS: left eye; DMD: Descemet membrane detachment. Declarations Ethics approval and consent to participate The study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (IRB00006761-M2018244) and conducted in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from their guardians. Consent for publication Not applicable. Availability of data and materials The dataset used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was supported by the National Natural Science Foundation of China (81800801 and 81970768). Authors' contributions All the surgical procedures were performed by JH. JH, TY and ZD contributed to the design of this work. TY, ZD, RP, GX and SM contributed to the collection and analysis of data. PZ conducted the laboratory research. TY and ZD drafted the work, and JH revised it. All authors read and approved the final manuscript. Acknowledgements Not applicable. References Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2018;93(6):1123–30. https://doi.org/10.1111/cge.13148 . Williams AL, Bohnsack BL. The Ocular Neural Crest: Specification, Migration, and Then What? 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Cite Share Download PDF Status: Published Journal Publication published 28 Dec, 2022 Read the published version in BMC Ophthalmology → Version 1 posted Editorial decision: Major revision 22 Nov, 2022 Reviews received at journal 17 Nov, 2022 Reviewers agreed at journal 02 Sep, 2022 Reviews received at journal 18 Aug, 2022 Reviewers agreed at journal 31 Jul, 2022 Reviews received at journal 17 Jul, 2022 Reviewers agreed at journal 17 Jul, 2022 Reviewers invited by journal 17 Jul, 2022 Editor assigned by journal 17 Jul, 2022 Editor invited by journal 17 Jun, 2022 Submission checks completed at journal 17 Jun, 2022 First submitted to journal 22 May, 2022 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 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-1681755","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":114253713,"identity":"ecafec11-456f-4599-8234-37cc8e1c047c","order_by":0,"name":"Ting Yu","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ting","middleName":"","lastName":"Yu","suffix":""},{"id":114253714,"identity":"abda2c18-523f-403f-8d1d-070e580908df","order_by":1,"name":"Zhihao Dai","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhihao","middleName":"","lastName":"Dai","suffix":""},{"id":114253715,"identity":"60fc611a-1c7e-4e48-908b-9f87802969f8","order_by":2,"name":"Rongmei Peng","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rongmei","middleName":"","lastName":"Peng","suffix":""},{"id":114253716,"identity":"53c7b27b-e779-4b39-9f25-839dff9eecb1","order_by":3,"name":"Gege Xiao","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gege","middleName":"","lastName":"Xiao","suffix":""},{"id":114253717,"identity":"7afb252e-6d1c-4636-8a21-5103d6844c75","order_by":4,"name":"Pei Zhang","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pei","middleName":"","lastName":"Zhang","suffix":""},{"id":114253718,"identity":"90946f30-0498-4fce-9f88-f4344f0122d6","order_by":5,"name":"Siyi Ma","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Siyi","middleName":"","lastName":"Ma","suffix":""},{"id":114253719,"identity":"ddac3447-6e8c-489f-9178-def7ed24f7ee","order_by":6,"name":"Jing Hong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACAxAhASTZ2JsPGCQY2PDw8zcQqYWP51hCwYeCNBnJGQeI0AICchI5Ch9nfDhsY9CQgF+LOXvv4RcWBXfs2iRyGDfzGJznMWA4wPjhYw5uLZY959IsJAyeJbfxvD1szGNwm8ecuYFZcuY2PA67kWNmIGFwOJmNPS8NrMWy4QAbMy9RWhhyzH/zGJzjMTiQQFCL8QOgFjs2jhwDwxkGB4jQcuaMGTCQDyewAQPZ4INBMo/kjIPN+P1yvMf4s8Sfw/by7aCo/GNnz8/ffPDDRzxagIBNWoKBIbEBIcDYgEspDDB//MDAYE9I1SgYBaNgFIxgAACYWVSQ2WRoXgAAAABJRU5ErkJggg==","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Hong","suffix":""}],"badges":[],"createdAt":"2022-05-22 12:44:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1681755/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1681755/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12886-022-02754-8","type":"published","date":"2022-12-28T18:07:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":22962149,"identity":"c2ba565e-e1dc-489f-a0cf-b1726e9b3e62","added_by":"auto","created_at":"2022-06-22 18:46:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2933955,"visible":true,"origin":"","legend":"\u003cp\u003eClinical features of the patients (\u003cstrong\u003ea\u003c/strong\u003e, \u003cstrong\u003ed\u003c/strong\u003e, \u003cstrong\u003em\u003c/strong\u003e, Patient 1 right eye, OD; \u003cstrong\u003eb\u003c/strong\u003e, \u003cstrong\u003ee\u003c/strong\u003e, \u003cstrong\u003en\u003c/strong\u003e, Patient 1 left eye, OS; \u003cstrong\u003ec\u003c/strong\u003e, \u003cstrong\u003ef\u003c/strong\u003e, \u003cstrong\u003eo\u003c/strong\u003e, Patient 2 OD; \u003cstrong\u003eg\u003c/strong\u003e, \u003cstrong\u003ej\u003c/strong\u003e, Patient 2 OS; \u003cstrong\u003eh\u003c/strong\u003e, \u003cstrong\u003ek\u003c/strong\u003e, Patient 3 OD; \u003cstrong\u003ei\u003c/strong\u003e, \u003cstrong\u003el\u003c/strong\u003e, Patient 3 OS) (\u003cstrong\u003ea\u003c/strong\u003e-\u003cstrong\u003ec\u003c/strong\u003e, \u003cstrong\u003eg\u003c/strong\u003e-\u003cstrong\u003ei\u003c/strong\u003e) Corneal opacities were observed under the slit lamp. In Patient 1, central and temporal opacities covering the pupil are shown, and the primary opacities are located in the inferior nasal and superior temporal quadrants in Patient 3. The right eye of Patient 2 exhibited severe corneal edema and opacity before keratoplasty, while the cornea was transparent in his left eye. Besides, iris abnormalities including corectopia (white mark), deformed pupil, polycoria, posterior embryotoxon (red arrow), iris atrophy and ectropion uvea could be seen. The red circle marked the excised cornea during PK, and the red line shows the section of histopathological examination. (\u003cstrong\u003ed\u003c/strong\u003e-\u003cstrong\u003ef\u003c/strong\u003e, \u003cstrong\u003ej\u003c/strong\u003e-\u003cstrong\u003el\u003c/strong\u003e) Representative AS-OCT images. The images were taken in the transverse direction and showed shallow anterior chamber, thickened cornea and anterior synechia (white arrow). In both eyes of Patient 1 and Patient 3, anterior synechia predominantly occurred in the temporal quadrant, where corneal opacities existed. In the right eye of Patient 2, an obscure interface between the DM and the stroma could be observed (white square). (\u003cstrong\u003em\u003c/strong\u003e-\u003cstrong\u003eo\u003c/strong\u003e) Overview images of both corneas of Patient 1 and the right cornea of Patient 2 under a light microscope. Edematous epithelium and stroma were shown. In Patient 1, the abnormal sections were in the temporal quadrant of both corneas, which was consistent with opaque areas (HE, original magnification × 40). In the right cornea of Patient 2, the Descemet membrane detachment (DMD) was observed with the peripheral interlayer splitting (PAS, original magnification × 40).\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-1681755/v1/bde1e87c554aad8e274cba3e.png"},{"id":22962148,"identity":"049aaba4-0aa9-4f39-9b3b-ca9ef37f5aa6","added_by":"auto","created_at":"2022-06-22 18:46:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2137263,"visible":true,"origin":"","legend":"\u003cp\u003eThe novel histological finding of the excised cornea buttons after PK At high magnification, we observed the splitting of the DM (black arrow), where the hypoplastic iris and a uniform, homogeneous, lightly stained basement membrane-like structure were inserted. (\u003cstrong\u003ea\u003c/strong\u003e: Patient 1 OD, PAS, original magnification × 100; \u003cstrong\u003eb\u003c/strong\u003e: Patient 1 OS, PAS, original magnification × 100; \u003cstrong\u003ec\u003c/strong\u003e: Patient 2 OD, PAS, original magnification × 100)\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-1681755/v1/757e2c6027fff36edca55e27.png"},{"id":44714941,"identity":"fe69db29-d547-44cb-9458-5354d59e4e5b","added_by":"auto","created_at":"2023-10-16 18:11:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2984226,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1681755/v1/6c96d383-c3c6-47d9-ada3-4dd6584c15af.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Axenfeld-Rieger syndrome：A novel histopathologic finding associated with corneal abnormalities","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAxenfeld-Rieger syndrome (ARS) is a rare kind of anterior segment dysgenesis (ASD) with an estimated prevalence of 1 in 50,000 to 100,000 newborn babies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The main pathogenesis of ARS is abnormal migration and differentiation of neural crest cells (NCCs) during the embryonic period, leading to multiple phenotypes of ARS [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The most common ocular features of ARS are posterior embryotoxon (caused by anteriorly displaced Schwalbe\u0026rsquo;s line) and iris hypoplasia (especially corectopia and polycoria). Moreover, patients may have accompanying systemic defects, including mild midface abnormalities, redundant umbilical skin, dental and cardiovascular abnormalities [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCorneal abnormalities, such as corneal opacity and edema, are considered the atypical features of ARS, which are caused by glaucoma or intraocular surgery in most reported cases [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Congenital corneal opacity (CCO) is rarely observed in ARS, while the exact mechanism remains unknown [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A study reported that CCO had been seen in ARS and other ASD (especially Peters anomaly) could stem from a similar underlying mechanism [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Besides, some patients with unexplained corneal endothelial abnormalities have been reported, but all of them were adults [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. It is challenging to explore the real cause of those abnormalities. Therefore, our current understanding of how ARS may affect the cornea is incomplete.\u003c/p\u003e \u003cp\u003eThe characteristic histopathologic features of ARS are prominent, anteriorly displaced Schwalbe\u0026rsquo;s line and tissue strands connecting peripheral iris and corneal limbus. Moreover, it was observed that the abnormal Schwalbe\u0026rsquo;s line was composed of dense collagen and ground substance covered by a layer that resembled the Descemet membrane (DM) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, due to the small number of patients, there are lack histopathological observations focusing on the corneal opacity that primarily occurs in ARS.\u003c/p\u003e \u003cp\u003eIn this study, we analyzed 3 cases (6 eyes) of ARS with various degrees of corneal abnormalities. After keratoplasty, we performed a histopathological examination on corneal tissues and presented a new finding, which might improve our understanding of this disease.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eThree patients (6 eyes) diagnosed with ARS complicating corneal opacity were retrospectively reviewed. All patients had undergone keratoplasty(penetrating keratoplasty, PK or Descemet stripping automated endothelial keratoplasty, DSAEK)unilaterally or bilaterally for irreversible endothelial decompensation at Peking University Third Hospital from May 2016 to January 2019. Besides, they had no surgical history or glaucoma prior to keratoplasty, which allowed us to observe the primary ocular appearance. The study was conducted following the revised Declaration of Helsinki. Ethics approval was obtained from the Institutional Review Board of Peking University Third Hospital. Informed consent was obtained from their guardians.\u003c/p\u003e \u003cp\u003ePatients were diagnosed with ARS if either of the following characteristics were observed in either eye [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]: (1) Iris hypoplasia including loss of iris stroma, polycoria, corectopia and ectropion uveae; (2) An appearance of posterior embryotoxon under slit-lamp examination in combination with peripheral anterior synechia. Systemic features such as midface dysmorphism, dental abnormality, and redundant periumbilical skin helped diagnose ARS.\u003c/p\u003e \u003cp\u003eThe data gathered concerning demographics (age at operation, gender), family histories, systemic abnormalities, preoperative and intraoperative data, including best-corrected visual acuity (BCVA) (logMAR), intraocular pressure (IOP) (Goldmann tonometer), slit-lamp biomicroscopy findings, anterior segment optical coherence tomography (AS-OCT, Visante, Carl Zeiss Meditec, Dublin, CA, USA) photographs. Gene sequencing was recommended for all patients, yet none of them were tested.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eHistopathology of surgical specimens\u003c/h2\u003e \u003cp\u003eCornea tissue (full-thickness cornea or endothelium/DM) of these patients underwent histopathological examination after surgery. Histopathologic procedures, including hematoxylin and eosin (H\u0026amp;E) stain and periodic acid-Schiff (PAS) stain were performed to obtain the pathologic features of the cornea sections. All the sections were examined using light microscopy.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e4 eyes of 2 males and 2 eyes of a female were included in our study. The mean age at operation was 7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43 years (ranged 6.3\u0026ndash;7.6 years). They were clinically diagnosed as ARS and showed characteristic systemic abnormalities, while none had a family history of ocular diseases. Two patients (Patient 1 and 3) were born with corneal opacity bilaterally. Except for the left eye of Patient 2, all eyes had developed irreversible endothelial decompensation. 3 eyes (Patient 1 bilateral eyes, OU, Patient 2 right eye, OD) were treated by PK, while 2 eyes (Patient 3 OU) underwent DSAEK.\u003c/p\u003e \u003cp\u003eAmong 5 eyes that developed irreversible endothelial decompensation, BCVA ranged from 0.9 to 0.2 before the occurrence of corneal edema and declined to a range of hand motions to 1.7 afterwards. Before the operation, all the eyes maintained normal intraocular pressure without medications.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical observation\u003c/h2\u003e \u003cp\u003eAll eyes showed iris abnormalities under a slit lamp microscope, including corectopia, polycoria, and stromal hypoplasia. Ectropion uveae was observed in the left eye of Patient 2. Both eyes of Patient 3 and the left eye of Patient 2 exhibited characteristic posterior embryotoxon, which was absent in Patient 1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eExcept for the left eye of Patient 2, corneas of all eyes presented with various degrees of edema. AS-OCT photographs of all eyes showed the peripheral anterior synechia, while in both eyes of 2 patients (Patient 1 and 3) the iris adhered to the quadrants where corneal opacities occurred (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). All these eyes showed marked shallow anterior chamber and thickened cornea. Besides, an obscure interface could be seen on AS-OCT images of the right eye of Patient 2, indicating the mild detachment of DM.\u003c/p\u003e \u003cp\u003eConfocal imaging was performed on the left eye of Patient 2. We observed endothelial cells with a normal hexagonal pattern but indistinct boundary and no primary endothelial lesion. Meanwhile, the average cell density was 2303 cell/mm\u003csup\u003e2\u003c/sup\u003e. The average cell density continuously declined to 1309 cell/mm\u003csup\u003e2\u003c/sup\u003e during a two-year follow-up period. Furthermore, the cornea remained transparent at the most recent clinic follow-up, and the eye did not develop glaucoma with regular use of topical ocular hypotensive medications.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eHistopathological findings\u003c/h2\u003e \u003cp\u003eH\u0026amp;E and PAS stained sections of 5 eyes that underwent keratoplasty and were observed under a light microscope. The endothelium/DM specimen removed from both eyes of Patient 3 after DSAEK showed an uneven thickness of DM and an absence of endothelium. We noted an anomalous structure in 3 eyes treated by PK (Patient 1 OU, Patient 2 OD). The structure was observed in the opaque area of both eyes of Patient 1 and the adherent area of the right eye of Patient 2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At high magnification, we found that the DMs of these 3 eyes were split and inserted by hypoplastic iris and a basement membrane-like structure (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Besides, we observed the detachment of the DM in the right eye of Patient 2 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we retrospectively studied 3 cases of ARS together with corneal abnormalities. The patients in our study had not developed glaucoma or had a history of intraocular surgery. We hoped to observe the keratopathy and histopathological changes directly caused by ARS to deepen our understanding of this disease.\u003c/p\u003e \u003cp\u003eDuring embryonic development, the NCCs and mesoderm cells migrate to the area between the surface ectoderm and the optic cup, contributing to the corneal stroma and endothelium, the iris stroma and the trabecular meshwork [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The development process of the posterior cornea and the iris are closely related, and the abnormalities in these processes can lead to corneal opacity and anterior synechia. A previous study on congenital corneal opacity found that the severity of the corneal opacity was positively correlated with the amount of iridocorneal adhesions [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In our study, the opaque areas corresponded to the adherent areas, indicating a closer relationship between these two signs. It can be speculated that in some ARS patients, the adherence of iris may occur along with the corneal abnormalities during the embryonic period.\u003c/p\u003e \u003cp\u003eWe made a novel histopathological finding which had never been reported before in ARS. In the eyes treated by PK, we observed the interlayer splitting of the DM with hypoplastic iris and a uniform, homogeneous, lightly stained basement membrane-like structure inserted in it. Besides, this feature happened to be in the area with corneal opacity and anterior synechia. Meanwhile, Ni et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] had made an analogous histopathological finding in a child diagnosed with Peters anomaly, which is caused by abnormal migration and differentiation of ocular NC cells. They observed the \u0026ldquo;multiple-layer\u0026rdquo; structures at the peripheral part of the DM, with pigmented tissues inside the layers. The highly similar histopathological appearance suggests the common underlying mechanism. Currently, it is commonly believed that three waves of cell migration produce anterior segment structures. Different waves of cells formed the corneal endothelium, the corneal stroma and the iris stroma, but these processes were under control of the same transcription factors and signaling pathways [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Accordingly, we speculated that the NCCs might migrate to the wrong location in these patients, leading to the mixture of hypoplasia iris and the DM. After that, the abnormal development of the NCCs caused the corneal opacities and anterior synechia at these sites. However, establishing the anterior ocular segment is a complicated process affected by multiple factors [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], and a complete understanding of this process remains elusive. Further studies are needed to illustrate the specific mechanism. Furthermore, we did not find the abnormal structure in the patient treated by DSAEK, where the procedures are more likely to ruin the primary structure of the posterior cornea and less likely to cover the abnormal area. Besides, this abnormal histopathologic feature may not appear in all ARS patients complicating corneal abnormalities.\u003c/p\u003e \u003cp\u003eFive eyes without the prior ocular disease (except ARS) or surgical history developed irreversible endothelial decompensation in our study. Endothelial decompensation had been found in several cases with ARS [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, in these cases, the damage to endothelial membrane could be explained by surgery or long-standing glaucoma. Besides, corneal guttae and beaten metal appearance of corneal endothelium were observed in several cases of ARS [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; however, it is still unclear whether this endothelial appearance is related to endothelial decompensation. We examined the endothelial cells in the left eye of Patient 2, and recorded the subsequent changes over the following two years. The result showed the cells with a normal hexagonal pattern but obscure boundary. Besides, neither corneal guttae nor the beaten metal appearance of the corneal endothelium was observed. The continuous decline in the cell count might suggest the existing damage despite the transparent cornea. This slight but progressive endothelial damage may exist in other ARS patients, yet existing theories could not explain it. It is also hard to determine whether it primarily occurred or is the result of a progression of the disease. The tissue strands extending from the edge of the corneal endothelium to peripheral iris are a major characteristic of ARS [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Accordingly, we hypothesized that traction of these tissue strands might cause irreversible corneal decompensation in these eyes. These tissue strands moved with the pupil and gradually lost corneal endothelial cells near the adhesion area. The surrounding endothelial cells were filled in afterwards. We found no analogous assumption in previous studies, and more research is needed to verify our opinion. Additionally, the histopathologic examination found the DMD in the right eye of Patient 2, who exhibited diffuse edema. The AS-OCT images before operation showed a weak adhesion between DM and posterior corneal stroma. DMD had been reported after penetrating keratoplasty (PK), especially in those with preexisting endothelial diseases [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Therefore, the operation procedures, pre-existing endothelial damage, and tissue strands' long-standing traction might jointly lead to the DMD we observed.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, 6 eyes with ARS were specifically described in our study. We focused on congenital corneal opacity and irreversible endothelial decompensation in these eyes and explored the underlying mechanism through histopathologic examination. Consequently, we made a novel histopathologic finding and found progressive endothelial damage in 1 patient. Our results may enhance the understanding of ARS and improve the prognosis of the patients with ARS complicating corneal abnormalities.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eARS: Axenfeld-Rieger syndrome; ASD: Anterior segment dysgenesis; NCCs: Neural crest cells; CCO: Congenital corneal opacity; DM: Descemet membrane; PK: Penetrating keratoplasty; DSAEK: Descemet stripping automated endothelial keratoplasty; BCVA: Best-corrected visual acuity; IOP: Intraocular pressure; AS-OCT: Anterior segment optical coherence tomography; H\u0026amp;E: Hematoxylin and eosin; PAS: Periodic acid-Schiff ; OU: bilateral eyes; OD: right eye; OS: left eye; DMD: Descemet membrane detachment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (IRB00006761-M2018244) and conducted in compliance with the principles of the Declaration of Helsinki. Informed consent was obtained from their guardians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China (81800801 and 81970768).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the surgical procedures were performed by JH. JH, TY and ZD contributed to the design of this work. TY, ZD, RP, GX and SM contributed to the collection and analysis of data. PZ conducted the laboratory research. TY and ZD drafted the work, and JH revised it. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSeifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2018;93(6):1123\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/cge.13148\u003c/span\u003e\u003cspan address=\"10.1111/cge.13148\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams AL, Bohnsack BL. The Ocular Neural Crest: Specification, Migration, and Then What? 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Surv Ophthalmol. 2020;65(3):279\u0026ndash;93. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.survophthal.2019.12.006\u003c/span\u003e\u003cspan address=\"10.1016/j.survophthal.2019.12.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Axenfeld-Rieger syndrome, histopathologic, congenital corneal opacity, endothelial decompensation","lastPublishedDoi":"10.21203/rs.3.rs-1681755/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1681755/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Axenfeld-Rieger syndrome (ARS) is a rare kind of anterior segment dysgenesis (ASD). The most common ocular features of ARS are posterior embryotoxon and iris hypoplasia, while some patients may manifest as corneal opacity and edema. However, the current understanding of how ARS affects the cornea is still incomplete. This study reports a novel histopathological finding of Axenfeld-Rieger syndrome (ARS), complicating corneal abnormalities, including congenital corneal opacity and irreversible endothelial decompensation.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This retrospective study included 6 eyes of 3 ARS patients who underwent keratoplasty for irreversible endothelial decompensation from May 2016 to January 2019. No eye had a history of surgery or glaucoma. We reviewed the data of epidemiology, clinical manifestations and pathological examinations.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Five eyes developed irreversible endothelial decompensation, among which 4 were born with corneal opacity. One eye exhibited transparent cornea but showed a continuous loss of endothelial cells in the absence of surgery and glaucoma thereafter. Anterior segment optical coherence tomography photographs showed that anterior synechia existed in the area with corneal opacities, where we found the interlayer splitting of the Descemet membrane inserted by hypoplastic iris and a basement membrane-like structure under a light microscope. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Anterior synechia might be associated with corneal abnormalities in ARS patients. The novel histopathologic finding revealed the internal relation between anterior segment dysgenesis and would help explore the inner mechanism of corneal abnormalities in ARS.\u003c/p\u003e","manuscriptTitle":"Axenfeld-Rieger syndrome：A novel histopathologic finding associated with corneal abnormalities","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-06-22 18:46:29","doi":"10.21203/rs.3.rs-1681755/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2022-11-22T13:02:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-11-17T06:19:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62b12a18-4418-4556-9f0e-5a018f708b5c","date":"2022-09-02T09:55:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-08-18T10:45:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"07bac69e-c3a6-4bbe-9d5a-20821c6f5c64","date":"2022-07-31T23:16:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2022-07-17T18:37:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"ace2000b-c150-464c-bcb0-5a8a863ee594","date":"2022-07-17T18:34:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-07-17T08:37:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-07-17T08:33:31+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2022-06-17T07:35:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-06-17T06:19:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2022-05-22T12:29:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c8e346cf-ef81-4727-a761-3643161f3901","owner":[],"postedDate":"June 22nd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T18:08:34+00:00","versionOfRecord":{"articleIdentity":"rs-1681755","link":"https://doi.org/10.1186/s12886-022-02754-8","journal":{"identity":"bmc-ophthalmology","isVorOnly":false,"title":"BMC Ophthalmology"},"publishedOn":"2022-12-28 18:07:06","publishedOnDateReadable":"December 28th, 2022"},"versionCreatedAt":"2022-06-22 18:46:29","video":"","vorDoi":"10.1186/s12886-022-02754-8","vorDoiUrl":"https://doi.org/10.1186/s12886-022-02754-8","workflowStages":[]},"version":"v1","identity":"rs-1681755","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1681755","identity":"rs-1681755","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}