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Purpose: To describe a rare case of clinically pigmented choroidal schwannoma with extraocular extension in an elderly patient. Observations: We report a case of a 79-year-old Black male who presented with a clinically pigmented, juxtapapillary choroidal tumor with concern for extraocular extension on standardized ocular echography. The lesion was concerning for choroidal melanoma with extraocular extension. He had no history of cancer or known genetic disease. After an extensive discussion of management options, he underwent enucleation of the left eye. Histopathology of the tumor showed non-pigmented cells with bland, spindle-shaped nuclei and areas of Antoni A pattern along with immunostaining consistent with choroidal schwannoma with extraocular extension. Conclusion: Choroidal schwannoma can mimic choroidal melanoma and can have a clinically pigmented appearance particularly in darkly complected individuals. This case highlights the importance of including choroidal schwannoma on the differential diagnosis for choroidal neoplasms, particularly in populations of individuals in whom melanoma is less common. Though more common in younger patients, choroidal schwannoma can present in elderly patients.

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Introduction: The systemic HIF-2 alpha inhibitor, belzutifan, has been approved for use in patients with von Hippel-Lindau disease (VHL)-associated renal cell carcinoma, central nervous system (CNS) hemangioblastomas, and pancreatic neuroendocrine tumors. This drug has also shown promise in controlling VHL retinal hemangioblastomas (RHs), but little work has been published on the use of the drug in this setting. Methods: We conducted a retrospective review of patients with VHL-associated RHs followed by the retina service at our institution who were treated with systemic belzutifan. Patient age, gender, genotype, presence of systemic tumors, indication for the drug, initial dose, adjusted dose, side effects, and tumor response were recorded. We also conducted a literature search for all manuscripts describing the effect of belzutifan on VHL-associated ocular tumors. Results: We identified 12 eyes of 7 patients with VHL-associated ocular tumors who were treated with belzutifan at our institution. Of these, 5 eyes of 3 patients had progressing ocular tumors when belzutifan was started. Of the 7 total patients, 2 were treated for renal cell carcinoma, 2 for CNS hemangioblastomas, 2 for RHs, and one for pancreatic neuroendocrine tumors. Initial dose was 120 mg PO daily in 6 patients and 80 mg PO daily in 1 patient. The dose was reduced in all but 1 patient due to side effects. The ocular tumors were controlled in all patients with an average follow-up of 13 months (range 4-24 months). Literature review identified 7 manuscripts that described belzutifan-mediated control of ocular tumors in patients with VHL-associated RHs in 21 patients. Conclusion: The drug belzutifan shows great promise for controlling RHs and preventing vision loss in patients with VHL. Further work needs to address the optimal dose, role of the drug as a neoadjuvant therapy, and long-term efficacy and tolerability of the drug in a larger cohort of patients with ocular tumors.

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While dysfunction and death of light-detecting photoreceptor cells underlie most inherited retinal dystrophies, knowledge of the species-specific details of human rod and cone photoreceptor cell development remains limited. Here, we generated retinal organoids carrying retinal disease-causing variants in NR2E3, as well as isogenic and unrelated controls. Organoids were sampled using single-cell RNA sequencing (scRNA-Seq) across the developmental window encompassing photoreceptor specification, emergence, and maturation. Using scRNA-Seq data, we reconstruct the rod photoreceptor developmental lineage and identify a branch point unique to the disease state. We show that the rod-specific transcription factor NR2E3 is required for the proper expression of genes involved in phototransduction, including rhodopsin, which is absent in divergent rods. NR2E3-null rods additionally misexpress several cone-specific phototransduction genes. Using joint multimodal single-cell sequencing, we further identify putative regulatory sites where rod-specific factors act to steer photoreceptor cell development. Finally, we show that rod-committed photoreceptor cells form and persist throughout life in a patient with NR2E3-associated disease. Importantly, these findings are strikingly different from those observed in Nr2e3 rodent models. Together, these data provide a road map of human photoreceptor development and leverage patient induced pluripotent stem cells to define the specific roles of rod transcription factors in photoreceptor cell emergence and maturation in health and disease.

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Organoides , Receptores Nucleares Huérfanos , Células Fotorreceptoras Retinianas Bastones , Humanos , Organoides/metabolismo , Organoides/patología , Células Fotorreceptoras Retinianas Bastones/metabolismo , Células Fotorreceptoras Retinianas Bastones/patología , Receptores Nucleares Huérfanos/genética , Receptores Nucleares Huérfanos/metabolismo , Células Fotorreceptoras Retinianas Conos/metabolismo , Células Fotorreceptoras Retinianas Conos/patología , Retina/metabolismo , Retina/patología , Retina/crecimiento & desarrollo , Diferenciación Celular , Fototransducción/genética , Análisis de la Célula Individual

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The effects of radiation retinopathy on the retinal vasculature have been well established; however, the literature describing the pathologic changes in the choriocapillaris is relatively lacking. In this report, we describe the histologic findings of a donor eye with a choroidal melanoma with special attention to the choriocapillaris. Clinical and histological findings, including immunohistochemistry and transmission electron microscopy, are described for the retina and choroid of a donor eye affected by radiation retinopathy secondary to treatment of choroidal melanoma. Cells within the tumor exhibited an epithelioid structure and balloon melanosomes. Notable infiltration of macrophages with elongated morphology was also observed. Atrophy of photoreceptors, retinal pigmented epithelium, and choriocapillaris was observed on the inferior edge of the lesion and extending past the tumor. The choriocapillaris endothelium showed more severe dropout at the periphery of the lesion where loss of fenestration, thickened cytosol, and degenerated pericytes were observed. Morphologic analysis revealed choriocapillaris loss with pronounced degeneration of choroidal pericytes. Understanding the differences in sensitivity to radiation injury between different cell types and different patients will provide better insight into radiation retinopathy.

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Von Hippel-Lindau (VHL) disease is a rare inherited cancer syndrome that results in the development of tumor formation in multiple systems. In the eye, retinal capillary hemangioma (RCH) can lead to severe vision loss. Retinopathy of prematurity (ROP) is likewise a rare disease in which abnormal retinal vasculature develops in premature infants. Hallmarks of this disease include temporal dragging of the macula and retinal vessels. Here, we describe a 36-year-old myopic woman with a known history of ROP who presented with a vitreous hemorrhage in the right eye. As the vitreous hemorrhage cleared, she was found to have not only a retinal tear but also a juxtapapillary RCH that lead to a diagnosis of VHL disease in the patient, her mother, and her aunt. This is the first reported case of an individual with concomitant ROP and RCH from VHL. Her vision was remarkably well preserved over 25 years of follow-up despite having a moderate-sized laser scar temporal to the disc from treating the juxtapapillary RCH, likely due to the temporal macular dragging from her underlying ROP. This case highlights the importance of being aware that rare diagnoses can co-exist, and one must be aware of the protean manifestations of VHL.

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The human choroid is a heterogeneous, highly vascular connective tissue that dysfunctions in age-related macular degeneration (AMD). In this study, we performed single-cell RNA sequencing on 21 human choroids, 11 of which were derived from donors with early atrophic or neovascular AMD. Using this large donor cohort, we identified new gene expression signatures and immunohistochemically characterized discrete populations of resident macrophages, monocytes/inflammatory macrophages and dendritic cells. These three immune populations demonstrated unique expression patterns for AMD genetic risk factors, with dendritic cells possessing the highest expression of the neovascular AMD-associated MMP9 gene. Additionally, we performed trajectory analysis to model transcriptomic changes across the choroidal vasculature, and we identified expression signatures for endothelial cells from choroidal arterioles and venules. Finally, we performed differential expression analysis between control, early atrophic AMD, and neovascular AMD samples, and we observed that early atrophic AMD samples had high expression of SPARCL1, a gene that has been shown to increase in response to endothelial damage. Likewise, neovascular endothelial cells harbored gene expression changes consistent with endothelial cell damage and demonstrated increased expression of the sialomucins CD34 and ENCM, which were also observed at the protein level within neovascular membranes. Overall, this study characterizes the molecular features of new populations of choroidal endothelial cells and mononuclear phagocytes in a large cohort of AMD and control human donors.

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Neovascularización Coroidal , Degeneración Macular Húmeda , Inhibidores de la Angiogénesis , Coroides , Neovascularización Coroidal/genética , Células Endoteliales , Humanos , Macrófagos , Transcriptoma/genética , Factor A de Crecimiento Endotelial Vascular , Agudeza Visual , Degeneración Macular Húmeda/complicaciones

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