Multiple problems: a case of Cohen syndrome VPS13B mutation causing bilateral spherical lenses combined with retinitis pigmentosa

Multiple problems: a case of Cohen syndrome VPS13B mutation causing bilateral spherical lenses combined with retinitis pigmentosa | 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 Multiple problems: a case of Cohen syndrome VPS13B mutation causing bilateral spherical lenses combined with retinitis pigmentosa Yifan Wang, Keqing Meng, Hong Chen, Xin Jin, Guoxing Yang, Gaoyang Ma, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5124059/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Cohen syndrome is a rare autosomal recessive disorder characterized by facial anomalies with or without microcephaly, non-progressive intellectual disability, hypotonia, ocular abnormalities, and neutropenia. Due to its low prevalence and diverse presentations, much information about the disease, including ocular manifestations, is not yet fully understood. To date, there is a paucity of literature on Cohen syndrome, which is characterized by predominantly ocular manifestations and typical manifestations in multiple systems throughout the body. Case Presentation: A 24-year-old male with a history of intellectual disability since childhood presented with decreased vision in both eyes for 2 years. He was diagnosed with bilateral spherical lens, bilateral subluxation of lens, bilateral complicated cataract, and bilateral retinitis pigmentosa. Cataract extraction combined with intraocular lens implantation was successful in both eyes, and vision improved after surgery. His underlying syndrome was studied genetically by whole exome sequencing. Genetic testing through whole-exome sequencing revealed a mutation in the VPS13B gene: c.6865 + 1G > T, confirming the diagnosis of Cohen syndrome. Conclusion Ophthalmologists should consider the diagnosis of Cohen syndrome in patients with developmental delay, spherical lens, and retinitis pigmentosa. A detailed ophthalmologic examination and general examination should be considered in such patients. Cohen syndrome VPS13B spherical lenses lens subluxation retinitis pigmentosa high myopia intellectual disability Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Cohen syndrome, a rare autosomal recessive disorder characterized by facial anomalies with or without microcephaly, nonprogressive intellectual disability, hypotonia, ocular anomalies, and neutropenia, has not been defined until the last 50 years; as a result, much about the disorder is not yet fully understood, and the typical clinical features of Cohen syndrome have been well described and involve multiple systems . 1–6 Gene testing can identify related systemic abnormalities and provide appropriate genetic counseling. This case report describes a patient who initially presented with bilateral concurrent cataracts and was also found to have bilateral lens subluxation, bilateral spherical lenses, and bilateral retinitis pigmentosa, along with intellectual disability. After cataract surgery, the patient’s vision improved. Cases with ocular symptoms as the primary manifestation and classic multi-system involvement of Cohen syndrome are extremely rare. Case Presentation A 24-year-old male with mental retardation presented with double vision for two years. There was no history of parental consanguineous marriage, no history of trauma, family history or other diseases. 158cm 63kg. Visual acuity examination was uncooperative. Intraocular pressure (IOP) was 12mmHg in the right eye and 14mmHg in the left eye. Slit-lamp biomicroscopy showed clouding of the lens with nystagmus in both eyes. Slit lamp biomicroscopy showed cloudy lens (C2N0P1) with nystagmus in both eyes, clear yellowish optic disc boundaries, scattered osteoblast-like pigmentation was seen in the retina, and the central macular reflection was not visible (Figure 1). Anterior segment OCT showed that the distance from the equator of the temporal lens to the ciliary processes was longer than that of the contralateral quadrant (Figure 2). UBM showed binocular lens clouding and incomplete dislocation of both lenses (Figure 3). Macular OCT: Refractive interstitial confusion was seen in both eyes, and the retinal structure was slightly disorganized in the macular region, with ellipsoidal band reflections missing, pigment epithelial reflections disorganized, and some areas of reflections missing (Figure 4). Ultrasound: vitreous clouding was seen in both eyes (Figure 5). Chest CT: Nodular shadows in the upper and lower lobes of the right lungs, with recommendations for follow up of the lower lobes of both lungs for cords and stripes, thickening of the right pleura, and fatty liver in the left pleural effusion. Blood cells showed a leukocyte count of 3.02 X109/L and a neutrophil count of 1. 52 X109/L. For psychological and physical reasons, the patient could not be examined for visual acuity, FFA, full-field electrophysiologic recordings of dark- and bright-field electroretinograms (ERGs), and visual fields, among other related tests. Gene exon sequencing revealed a pure mutation in the patient's VPS13B gene, consistent with Cohen syndrome, and heterozygous mutations in his father, mother, and brother (Figure 6). Therefore, the diagnosis was Cohen syndrome, spherical lens in both eyes, incomplete dislocation of lens in both eyes, concurrent cataract in both eyes, and retinitis pigmentosa in both eyes. The patient underwent cataract ultrasonography + capsular bag tension ring implantation + IOL implantation + anterior vitrectomy + peripheral iridectomy + vitreous cavity injection (tretinoin injection) in both eyes under general anesthesia successively (Figure 7), and the patient and his family members felt that their visual acuity had improved after the operation. Discussion and Conclusions Cohen syndrome (Online Mendelian Inheritance in Man (OMIM) entry number 216550) is an ever-so-rare systemic disorder caused by an autosomal recessive (AR) mutation in the vesicular protein sorting 13 homolog B (VPS13B, also known as COH1) gene on chromosome 8q22.2. VPS13B is a transmembrane protein that plays a role in intracellular vesicle-mediated protein transport and sorting, as well as in the development and function of the eye, the blood system, and the central nervous system. Thus the clinical manifestations leading to Cohen syndrome involve multiple systems. Here, we present the case of a 24-year-old Chinese man with classic manifestations of Cohen syndrome. The patient had numerous ocular abnormalities such as bilateral spherical lenses, bilateral lens dislocations, bilateral concurrent cataracts, bilateral high myopia, and bilateral retinitis pigmentosa, as well as systemic abnormalities such as short stature and obesity, mental retardation, and neutropenia. It is hypothesized that spherical lens is the cause of high myopia, lens dislocation, combined with binocular retinitis pigmentosa thereby leading to the development of concurrent cataracts. Microspherical lens (MSP) is a rare genetic disorder that can occur in WeillMarchesani syndrome, Marfan syndrome, Alport syndrome, and Klinefelter syndrome, most commonly in Weill-Marchesani syndrome. However, Cohen syndrome is rarely reported. Rodrigues and Chu et al. reported a related condition of spherical lenses in Cohen syndrome; therefore, we hypothesized that the VPS13B mutation may also contribute to the development of spherical lenses. Spherical lenses are characterized by spherical shape, increased anteroposterior distance, and decreased equatorial diameter (ED). 7–11 Due to abnormal relaxation of the suspensory ligament of the lens in such patients, the position of the lens changes, leading to dislocation or subluxation of the lens, with an incidence of approximately 44.4%. 11 At the same time, the spherical lens causes the refractive state of the patient to be highly myopic, and due to the relaxation of the suspensory ligament of the lens, there are often accommodation defects. Together with high myopia, retinal dystrophy and cataract constitute the main ophthalmic features of Cohen syndrome. The retinal dystrophy is most likely due to a VPS13B mutation, and the change is progressive, and eventually, vision may be limited to finger counting and light perception; correction of refractive errors has a positive effect on development because of the early onset of high myopia. 12–17 However, there is no available effective treatment to stop the progression of retinitis pigmentosa. Patients should undergo regular detailed ophthalmologic examinations to evaluate for refractive error or retinal dystrophy. The prevalence of cataracts in the patient population with Cohen's syndrome is approximately 64%, and cataracts may occur in such patients in early adulthood or even in childhood. 12,18 In most forms of retinitis pigmentosa, cataracts are considered a complication of retinal degeneration. 19,20 However, Lhussiez V et al. have experimentally suggested that cataracts in Cohen's syndrome may not be secondary to retinal dystrophy but may be due to a specific defect in lens homeostasis, not a mutation in VPS13B, but other factors in the genetic background of patients with Cohen's syndrome that may contribute to the disease. 21 Retinal dystrophy with cataracts must be carefully considered as a treatment for retinal dystrophy due to potential postoperative complications such as near-term inflammation of the uvea, and dislocation of the capsular bag complex of the IOL at a distant stage. Thus, cataract surgery is an important issue in the diagnosis and management of Cohen's syndrome 22–24 . In terms of patient-related systemic conditions, the literature notes that all patients with Cohen syndrome have some degree of mental retardation, with up to 22% having severe developmental delays. 5 And hematological leukopenia, particularly neutropenia, is a common feature of Cohen syndrome, where patients may develop neutrophilia in response to bacterial infections.25 Recombinant human granulocyte colony-stimulating factor (rHG-CSF) may be used in the treatment of neutropenia. In addition, blood pressure, fasting glucose levels, lipid metabolism, and hemoglobin A1C levels should be monitored annually as these patients are prone to insulin resistance. 26 At present, most of the related literatures on Cohen syndrome are only with some ocular manifestations or accompanied by some systemic manifestations. This case report adds value for future clinical practice by providing a variety of classic ophthalmic and systemic manifestations of Cohen syndrome. Through continued monitoring and discussion of these findings, we hope to be able to draw a more complete and accurate picture of the presentation of Cohen syndrome and contribute to the limited literature available. Abbreviations IOL Intraocular lens OCT Optical coherence tomography UBM Ultrasound biomicroscopy FFA Fluorescein fundus angiography Declarations All methods were performed in accordance with the ethical standards as laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was obtained from all participants .Include a statement on ethics approval and consent. Ethics approval and consent to participate The study was approved by the review board of the Hebei Eye Hospital. Consent for publication Written informed consent was obtained from the patient and his parents for publication of this case report. Data availability Data is provided within the manuscript or supplementary information fIles. Competing interests The authors declare no competing interests. Funding This work was supported by the Key Science and Technology Research Program of Hebei Provincial Health Commission under Grant number 20191048. Authors' contributions YFW was a major contributor in writing the manuscript. KQM and HC reviewed and revised the content of the article. XJ and GXY polished the content of the article. GYM, YC, CYZ and CCZ photographed and analyzed relevant examinations. MX and PJG was responsible for following up and communicating with the patient for regular reviews. LFW and WLZ revised and confirmed the final version.All authors read and approved the final manuscript. Acknowledgements Not applicable Authors' information YFW is a postgraduate student at Hebei Medical University. References Cohen MM, Hall BD, Smith DW, Graham CB, Lampert KJ. A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular, and limb anomalies. J Pediatr . 1973;83(2):280-284. doi:10.1016/s0022-3476(73)80493-7 Carey JC, Hall BD. Confirmation of the Cohen syndrome. J Pediatr . 1978;93(2):239-244. doi:10.1016/s0022-3476(78)80504-6 Norio R, Raitta C, Lindahl E. Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity. Clin Genet . 1984;25(1):1-14. doi:10.1111/j.1399-0004.1984.tb00456.x Rodrigues JM, Fernandes HD, Caruthers C, Braddock SR, Knutsen AP. Cohen Syndrome: Review of the Literature. Cureus . 2018;10(9):e3330. doi:10.7759/cureus.3330 Kivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet . 2001;102(2):125-135. doi:10.1002/1096-8628(20010801)102:23.0.co;2-0 Kolehmainen J, Wilkinson R, Lehesjoki AE, et al. Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet . 2004;75(1):122-127. doi:10.1086/422197 Chan RTY, Collin HB. Microspherophakia. Clin Exp Optom . 2002;85(5):294-299. doi:10.1111/j.1444-0938.2002.tb03085.x Yang J, Fan Q, Chen J, et al. The efficacy of lens removal plus IOL implantation for the treatment of spherophakia with secondary glaucoma. Br J Ophthalmol . 2016;100(8):1087-1092. doi:10.1136/bjophthalmol-2015-307298 Ndoye Roth PA, Toure SA, Kane H, et al. [Isolated microspherophakia in a Senegalese family]. J Fr Ophtalmol . 2017;40(2):110-114. doi:10.1016/j.jfo.2016.09.019 Muralidhar R, Ankush K, Vijayalakshmi P, George VP. Visual outcome and incidence of glaucoma in patients with microspherophakia. Eye (Lond) . 2015;29(3):350-355. doi:10.1038/eye.2014.250 Yu X, Chen W, Xu W. Diagnosis and treatment of microspherophakia. J Cataract Refract Surg . 2020;46(12):1674-1679. doi:10.1097/j.jcrs.0000000000000334 Taban M, Memoracion-Peralta DSA, Wang H, Al-Gazali LI, Traboulsi EI. Cohen syndrome: report of nine cases and review of the literature, with emphasis on ophthalmic features. J AAPOS . 2007;11(5):431-437. doi:10.1016/j.jaapos.2007.01.118 Summanen P, Kivitie-Kallio S, Norio R, Raitta C, Kivelä T. Mechanisms of myopia in Cohen syndrome mapped to chromosome 8q22. Invest Ophthalmol Vis Sci . 2002;43(5):1686-1693. Kivitie-Kallio S, Summanen P, Raitta C, Norio R. Ophthalmologic findings in Cohen syndrome. A long-term follow-up. Ophthalmology . 2000;107(9):1737-1745. doi:10.1016/s0161-6420(00)00279-7 Chandler KE, Biswas S, Lloyd IC, Parry N, Clayton-Smith J, Black GCM. The ophthalmic findings in Cohen syndrome. Br J Ophthalmol . 2002;86(12):1395-1398. doi:10.1136/bjo.86.12.1395 Nasser F, Kurtenbach A, Biskup S, Weidensee S, Kohl S, Zrenner E. Ophthalmic features of retinitis pigmentosa in Cohen syndrome caused by pathogenic variants in the VPS13B gene. Acta Ophthalmol . 2020;98(3):e316-e321. doi:10.1111/aos.14255 Vilares-Morgado R, Ferreira AM, Santos-Silva R, Quental R, Carneiro Â, Estrela-Silva S. Cohen Syndrome: Novel VPS13B Genetic Variants in a Male Portuguese Patient with Pigmentary Retinopathy. Case Rep Ophthalmol . 2023;14(1):519-527. doi:10.1159/000533974 Douzgou S, Samples JR, Georgoudi N, Petersen MB. Ophthalmic findings in the Greek isolate of Cohen syndrome. Am J Med Genet A . 2011;155A(3):534-539. doi:10.1002/ajmg.a.33797 Fishman GA, Anderson RJ, Lourenco P. Prevalence of posterior subcapsular lens opacities in patients with retinitis pigmentosa. Br J Ophthalmol . 1985;69(4):263-266. doi:10.1136/bjo.69.4.263 Fujiwara K, Ikeda Y, Murakami Y, et al. Risk Factors for Posterior Subcapsular Cataract in Retinitis Pigmentosa. Invest Ophthalmol Vis Sci . 2017;58(5):2534-2537. doi:10.1167/iovs.17-21612 Lhussiez V, Dubus E, Cesar Q, et al. Cohen Syndrome-Associated Cataract Is Explained by VPS13B Functions in Lens Homeostasis and Is Modified by Additional Genetic Factors. Invest Ophthalmol Vis Sci . 2020;61(11):18. doi:10.1167/iovs.61.11.18 Nelson ML, Martidis A. Managing cystoid macular edema after cataract surgery. Curr Opin Ophthalmol . 2003;14(1):39-43. doi:10.1097/00055735-200302000-00007 Dikopf MS, Chow CC, Mieler WF, Tu EY. Cataract extraction outcomes and the prevalence of zonular insufficiency in retinitis pigmentosa. Am J Ophthalmol . 2013;156(1):82-88.e2. doi:10.1016/j.ajo.2013.02.002 Davies EC, Pineda R. Cataract surgery outcomes and complications in retinal dystrophy patients. Can J Ophthalmol . 2017;52(6):543-547. doi:10.1016/j.jcjo.2017.04.002 Kivitie-Kallio S, Rajantie J, Juvonen E, Norio R. Granulocytopenia in Cohen syndrome. Br J Haematol . 1997;98(2):308-311. doi:10.1046/j.1365-2141.1997.2323049.x Momtazmanesh S, Rayzan E, Shahkarami S, Rohlfs M, Klein C, Rezaei N. A novel VPS13B mutation in Cohen syndrome: a case report and review of literature. BMC Med Genet . 2020;21(1):140. doi:10.1186/s12881-020-01075-1 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 Apr, 2025 Reviews received at journal 22 Mar, 2025 Reviews received at journal 17 Mar, 2025 Reviewers agreed at journal 10 Mar, 2025 Reviewers agreed at journal 22 Feb, 2025 Reviews received at journal 02 Jan, 2025 Reviewers agreed at journal 15 Dec, 2024 Reviewers invited by journal 12 Dec, 2024 Editor invited by journal 05 Dec, 2024 Editor assigned by journal 26 Sep, 2024 Submission checks completed at journal 25 Sep, 2024 First submitted to journal 25 Sep, 2024 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-5124059","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":446662078,"identity":"9c2ceb49-77c7-4b76-890a-e3be0d026d17","order_by":0,"name":"Yifan Wang","email":"","orcid":"","institution":"Hebei Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yifan","middleName":"","lastName":"Wang","suffix":""},{"id":446662080,"identity":"f1a0f99d-2047-46d4-890a-348fed7b7d57","order_by":1,"name":"Keqing Meng","email":"","orcid":"","institution":"Hebei Eye Hospital, Hebei Provincial Clinical Research Center for Eye 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Diseases","correspondingAuthor":false,"prefix":"","firstName":"Wulin","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2024-09-20 13:36:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5124059/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5124059/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82028035,"identity":"11db508e-38fc-41cb-85d4-f7b9bbee395a","added_by":"auto","created_at":"2025-05-06 06:55:23","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":103645,"visible":true,"origin":"","legend":"\u003cp\u003eAnterior segment photography showed clouding of the lens in both eyes and incomplete dislocation of the lens in both eyes.\u003c/p\u003e\n\u003cp\u003eFundus photography showed clear, yellowish optic discs, scattered osteoclast-like pigmentation in the retina, and no central macular reflection.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5124059/v1/19a2ba4918128d9778e46e89.jpg"},{"id":82028030,"identity":"42a14b39-933c-42f8-9849-726dc63a0816","added_by":"auto","created_at":"2025-05-06 06:55:22","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44841,"visible":true,"origin":"","legend":"\u003cp\u003eAnterior segment oct suggests that the distance from the equatorial portion of the lens to the ciliary processes is longer in the temporal side than in the contralateral quadrant.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5124059/v1/f31288a0a440eb4a9d7dfbc2.jpg"},{"id":82028632,"identity":"ce3b4d72-0776-466c-88ec-a12f3b05c257","added_by":"auto","created_at":"2025-05-06 07:03:22","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":96701,"visible":true,"origin":"","legend":"\u003cp\u003eUBM shows clouding of the lens in both eyes and incomplete dislocation of the lens in both eyes.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5124059/v1/16bcfc1575c3dbcfd13417a6.jpg"},{"id":82028634,"identity":"ec9b5d3d-7f41-46b3-9807-ca2c0e838aaf","added_by":"auto","created_at":"2025-05-06 07:03:23","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":232816,"visible":true,"origin":"","legend":"\u003cp\u003eMacular OCT showed: Refractive interstices in both eyes were seen to be unclear, and the retinal structure in the macular region was vaguely seen to be slightly disorganized, with ellipsoidal bands of reflection missing, pigment epithelium reflection disorganized, and reflection missing in some areas.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5124059/v1/57e377331ecb567e0a732b5d.jpg"},{"id":82028633,"identity":"27619c26-e877-48bd-bdd7-ec6ee575fae6","added_by":"auto","created_at":"2025-05-06 07:03:22","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":53633,"visible":true,"origin":"","legend":"\u003cp\u003eUltrasound: vitreous clouding in both eyes.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5124059/v1/fe5d836c2e40f1e20ae09bb6.jpg"},{"id":82028031,"identity":"dab47a52-717c-4c8c-9066-f916e09ec6f5","added_by":"auto","created_at":"2025-05-06 06:55:22","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":80185,"visible":true,"origin":"","legend":"\u003cp\u003eThe genetic results suggested that the patient had a pure mutation in the VPS13B gene and that her parents were heterozygous for the mutation with her brother.\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5124059/v1/fe0da96dd6c1607d69d86237.jpg"},{"id":82028034,"identity":"a4b4aa46-c271-4add-afcb-cd82fead86ed","added_by":"auto","created_at":"2025-05-06 06:55:22","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":136403,"visible":true,"origin":"","legend":"\u003cp\u003eCataract ultrasonography + capsular bag tension ring implantation + IOL implantation + anterior vitrectomy + peripheral iridectomy + vitreous cavity injection in both eyes under general anesthesia.\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5124059/v1/faff236818c09bdc5299466b.jpg"},{"id":82028635,"identity":"0d14858d-4e12-44de-ac2b-28ba2f542076","added_by":"auto","created_at":"2025-05-06 07:03:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1211411,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5124059/v1/a362fd7e-40e0-4143-b595-8b48432698e9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Multiple problems: a case of Cohen syndrome VPS13B mutation causing bilateral spherical lenses combined with retinitis pigmentosa","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCohen syndrome, a rare autosomal recessive disorder characterized by facial anomalies with or without microcephaly, nonprogressive intellectual disability, hypotonia, ocular anomalies, and neutropenia, has not been defined until the last 50 years; as a result, much about the disorder is not yet fully understood, and the typical clinical features of Cohen syndrome have been well described and involve multiple systems .\u0026nbsp;\u003csup\u003e1\u0026ndash;6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eGene testing can identify related systemic abnormalities and provide appropriate genetic counseling. This case report describes a patient who initially presented with bilateral concurrent cataracts and was also found to have bilateral lens subluxation, bilateral spherical lenses, and bilateral retinitis pigmentosa, along with intellectual disability. After cataract surgery, the patient\u0026rsquo;s vision improved. Cases with ocular symptoms as the primary manifestation and classic multi-system involvement of Cohen syndrome are extremely rare.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 24-year-old male with mental retardation presented with double vision for two years. There was no history of parental consanguineous marriage, no history of trauma, family history or other diseases. 158cm 63kg. Visual acuity examination was uncooperative. Intraocular pressure (IOP) was 12mmHg in the right eye and 14mmHg in the left eye. Slit-lamp biomicroscopy showed clouding of the lens with nystagmus in both eyes. Slit lamp biomicroscopy showed cloudy lens (C2N0P1) with nystagmus in both eyes, clear yellowish optic disc boundaries, scattered osteoblast-like pigmentation was seen in the retina, and the central macular reflection was not visible (Figure 1). Anterior segment OCT showed that the distance from the equator of the temporal lens to the ciliary processes was longer than that of the contralateral quadrant (Figure 2). UBM showed binocular lens clouding and incomplete dislocation of both lenses (Figure 3). Macular OCT: Refractive interstitial confusion was seen in both eyes, and the retinal structure was slightly disorganized in the macular region, with ellipsoidal band reflections missing, pigment epithelial reflections disorganized, and some areas of reflections missing (Figure 4). Ultrasound: vitreous clouding was seen in both eyes (Figure 5). Chest CT: Nodular shadows in the upper and lower lobes of the right lungs, with recommendations for follow up of the lower lobes of both lungs for cords and stripes, thickening of the right pleura, and fatty liver in the left pleural effusion. Blood cells showed a leukocyte count of 3.02 X109/L and a neutrophil count of 1. 52 X109/L. For psychological and physical reasons, the patient could not be examined for visual acuity, FFA, full-field electrophysiologic recordings of dark- and bright-field electroretinograms (ERGs), and visual fields, among other related tests. Gene exon sequencing revealed a pure mutation in the patient's VPS13B gene, consistent with Cohen syndrome, and heterozygous mutations in his father, mother, and brother (Figure 6).\u003c/p\u003e\n\u003cp\u003eTherefore, the diagnosis was Cohen syndrome, spherical lens in both eyes, incomplete dislocation of lens in both eyes, concurrent cataract in both eyes, and retinitis pigmentosa in both eyes. The patient underwent cataract ultrasonography + capsular bag tension ring implantation + IOL implantation + anterior vitrectomy + peripheral iridectomy + vitreous cavity injection (tretinoin injection) in both eyes under general anesthesia successively (Figure 7), and the patient and his family members felt that their visual acuity had improved after the operation.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eCohen syndrome (Online Mendelian Inheritance in Man (OMIM) entry number 216550) is an ever-so-rare systemic disorder caused by an autosomal recessive (AR) mutation in the vesicular protein sorting 13 homolog B (VPS13B, also known as COH1) gene on chromosome 8q22.2. VPS13B is a transmembrane protein that plays a role in intracellular vesicle-mediated protein transport and sorting, as well as in the development and function of the eye, the blood system, and the central nervous system. Thus the clinical manifestations leading to Cohen syndrome involve multiple systems. Here, we present the case of a 24-year-old Chinese man with classic manifestations of Cohen syndrome. The patient had numerous ocular abnormalities such as bilateral spherical lenses, bilateral lens dislocations, bilateral concurrent cataracts, bilateral high myopia, and bilateral retinitis pigmentosa, as well as systemic abnormalities such as short stature and obesity, mental retardation, and neutropenia. It is hypothesized that spherical lens is the cause of high myopia, lens dislocation, combined with binocular retinitis pigmentosa thereby leading to the development of concurrent cataracts.\u003c/p\u003e\n\u003cp\u003eMicrospherical lens (MSP) is a rare genetic disorder that can occur in WeillMarchesani syndrome, Marfan syndrome, Alport syndrome, and Klinefelter syndrome, most commonly in Weill-Marchesani syndrome. However, Cohen syndrome is rarely reported. Rodrigues and Chu et al. reported a related condition of spherical lenses in Cohen syndrome; therefore, we hypothesized that the VPS13B mutation may also contribute to the development of spherical lenses. Spherical lenses are characterized by spherical shape, increased anteroposterior distance, and decreased equatorial diameter (ED).\u003csup\u003e7–11\u003c/sup\u003e Due to abnormal relaxation of the suspensory ligament of the lens in such patients, the position of the lens changes, leading to dislocation or subluxation of the lens, with an incidence of approximately 44.4%.\u003csup\u003e11\u003c/sup\u003e At the same time, the spherical lens causes the refractive state of the patient to be highly myopic, and due to the relaxation of the suspensory ligament of the lens, there are often accommodation defects. Together with high myopia, retinal dystrophy and cataract constitute the main ophthalmic features of Cohen syndrome. The retinal dystrophy is most likely due to a VPS13B mutation, and the change is progressive, and eventually, vision may be limited to finger counting and light perception; correction of refractive errors has a positive effect on development because of the early onset of high myopia.\u003csup\u003e12–17\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eHowever, there is no available effective treatment to stop the progression of retinitis pigmentosa. Patients should undergo regular detailed ophthalmologic examinations to evaluate for refractive error or retinal dystrophy. The prevalence of cataracts in the patient population with Cohen's syndrome is approximately 64%, and cataracts may occur in such patients in early adulthood or even in childhood.\u003csup\u003e12,18\u003c/sup\u003e In most forms of retinitis pigmentosa, cataracts are considered a complication of retinal degeneration.\u003csup\u003e19,20\u003c/sup\u003eHowever, Lhussiez V et al. have experimentally suggested that cataracts in Cohen's syndrome may not be secondary to retinal dystrophy but may be due to a specific defect in lens homeostasis, not a mutation in VPS13B, but other factors in the genetic background of patients with Cohen's syndrome that may contribute to the disease.\u003csup\u003e21\u003c/sup\u003e Retinal dystrophy with cataracts must be carefully considered as a treatment for retinal dystrophy due to potential postoperative complications such as near-term inflammation of the uvea, and dislocation of the capsular bag complex of the IOL at a distant stage. Thus, cataract surgery is an important issue in the diagnosis and management of Cohen's syndrome\u003csup\u003e22–24\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn terms of patient-related systemic conditions, the literature notes that all patients with Cohen syndrome have some degree of mental retardation, with up to 22% having severe developmental delays.\u003csup\u003e5\u003c/sup\u003e And hematological leukopenia, particularly neutropenia, is a common feature of Cohen syndrome, where patients may develop neutrophilia in response to bacterial infections.25 Recombinant human granulocyte colony-stimulating factor (rHG-CSF) may be used in the treatment of neutropenia. In addition, blood pressure, fasting glucose levels, lipid metabolism, and hemoglobin A1C levels should be monitored annually as these patients are prone to insulin resistance.\u003csup\u003e26\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eAt present, most of the related literatures on Cohen syndrome are only with some ocular manifestations or accompanied by some systemic manifestations. This case report adds value for future clinical practice by providing a variety of classic ophthalmic and systemic manifestations of Cohen syndrome. Through continued monitoring and discussion of these findings, we hope to be able to draw a more complete and accurate picture of the presentation of Cohen syndrome and contribute to the limited literature available.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIOL Intraocular lens\u003c/p\u003e\n\u003cp\u003eOCT\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eOptical coherence tomography\u003c/p\u003e\n\u003cp\u003eUBM Ultrasound biomicroscopy\u003c/p\u003e\n\u003cp\u003eFFA Fluorescein fundus angiography\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAll methods were performed in accordance with the ethical standards as laid down in the Declaration of Helsinki and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all participants .Include a statement on ethics approval and consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the review board of the Hebei Eye Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient and his parents for\u0026nbsp;\u003c/p\u003e\n\u003cp\u003epublication of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eData availability\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information fIles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Key Science and Technology Research Program of Hebei Provincial Health Commission under Grant number 20191048.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors' contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYFW was a major contributor in writing the manuscript.\u0026nbsp;KQM and HC reviewed and revised the content of the article. XJ and GXY polished the content of the article. GYM, YC, CYZ and CCZ photographed and analyzed relevant examinations. MX and PJG was responsible for following up and communicating with the patient for regular reviews. LFW and WLZ revised and confirmed the final version.All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors' information\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYFW is a postgraduate student at Hebei Medical University.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCohen MM, Hall BD, Smith DW, Graham CB, Lampert KJ. 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Managing cystoid macular edema after cataract surgery. \u003cem\u003eCurr Opin Ophthalmol\u003c/em\u003e. 2003;14(1):39-43. doi:10.1097/00055735-200302000-00007\u003c/li\u003e\n\u003cli\u003eDikopf MS, Chow CC, Mieler WF, Tu EY. Cataract extraction outcomes and the prevalence of zonular insufficiency in retinitis pigmentosa. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e. 2013;156(1):82-88.e2. doi:10.1016/j.ajo.2013.02.002\u003c/li\u003e\n\u003cli\u003eDavies EC, Pineda R. Cataract surgery outcomes and complications in retinal dystrophy patients. \u003cem\u003eCan J Ophthalmol\u003c/em\u003e. 2017;52(6):543-547. doi:10.1016/j.jcjo.2017.04.002\u003c/li\u003e\n\u003cli\u003eKivitie-Kallio S, Rajantie J, Juvonen E, Norio R. Granulocytopenia in Cohen syndrome. \u003cem\u003eBr J Haematol\u003c/em\u003e. 1997;98(2):308-311. doi:10.1046/j.1365-2141.1997.2323049.x\u003c/li\u003e\n\u003cli\u003eMomtazmanesh S, Rayzan E, Shahkarami S, Rohlfs M, Klein C, Rezaei N. A novel VPS13B mutation in Cohen syndrome: a case report and review of literature. \u003cem\u003eBMC Med Genet\u003c/em\u003e. 2020;21(1):140. doi:10.1186/s12881-020-01075-1\u003c/li\u003e\n\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":"Cohen syndrome, VPS13B, spherical lenses, lens subluxation, retinitis pigmentosa, high myopia, intellectual disability","lastPublishedDoi":"10.21203/rs.3.rs-5124059/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5124059/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCohen syndrome is a rare autosomal recessive disorder characterized by facial anomalies with or without microcephaly, non-progressive intellectual disability, hypotonia, ocular abnormalities, and neutropenia. Due to its low prevalence and diverse presentations, much information about the disease, including ocular manifestations, is not yet fully understood. To date, there is a paucity of literature on Cohen syndrome, which is characterized by predominantly ocular manifestations and typical manifestations in multiple systems throughout the body.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e \u003cp\u003eA 24-year-old male with a history of intellectual disability since childhood presented with decreased vision in both eyes for 2 years. He was diagnosed with bilateral spherical lens, bilateral subluxation of lens, bilateral complicated cataract, and bilateral retinitis pigmentosa. Cataract extraction combined with intraocular lens implantation was successful in both eyes, and vision improved after surgery. His underlying syndrome was studied genetically by whole exome sequencing. Genetic testing through whole-exome sequencing revealed a mutation in the VPS13B gene: c.6865\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T, confirming the diagnosis of Cohen syndrome.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOphthalmologists should consider the diagnosis of Cohen syndrome in patients with developmental delay, spherical lens, and retinitis pigmentosa. A detailed ophthalmologic examination and general examination should be considered in such patients.\u003c/p\u003e","manuscriptTitle":"Multiple problems: a case of Cohen syndrome VPS13B mutation causing bilateral spherical lenses combined with retinitis pigmentosa","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 06:55:18","doi":"10.21203/rs.3.rs-5124059/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-23T04:18:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-22T11:58:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-17T10:11:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"175090067935806124542849021217381371887","date":"2025-03-10T16:28:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"56646056514110840675285259036516065174","date":"2025-02-22T14:30:17+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-01-02T12:30:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35431219985565698058959889171702678974","date":"2024-12-16T01:10:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-12-12T11:59:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-12-05T05:16:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-26T16:58:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-26T01:25:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2024-09-26T01:24:22+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":"e01e89a5-9557-4e88-bfec-59bb34c25c5c","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-06-11T03:53:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-06 06:55:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5124059","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5124059","identity":"rs-5124059","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}