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Brain tumors are the leading cause of cancer-related death in children, where low-grade gliomas (LGGs) predominate. One common hereditary cause for LGGs involves neurofibromatosis-1 (NF1) gene mutation, as seen in individuals with the NF1 cancer predisposition syndrome. As such, children with NF1 are at increased risk of developing LGGs of the optic pathway, brainstem, cerebellum, and midline brain structures. Using genetically engineered mouse models, studies have revealed both cell-intrinsic (MEK signaling) and stromal dependencies that underlie their formation and growth. Importantly, these dependencies represent vulnerabilities against which targeted agents can be used for preclinical investigation prior to clinical translation.

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MEK inhibitors (MEKi) represent innovative and promising treatments for managing manifestations of neurofibromatosis type 1 (NF1). To mitigate potential ophthalmic side effects, such as MEKi-associated retinopathy (MEKAR), patients undergoing MEKi therapy routinely receive ophthalmology evaluations. Our study aims to assess the necessity of this regular screening within a predominantly pediatric NF1 population by examining the occurrence of ocular adverse events (OAE). A retrospective study evaluated 45 NF1 patients receiving MEKi. Inclusion criteria included baseline and follow-up examinations following the initiation of MEKi therapy. At each assessment, a comprehensive eye evaluation was performed, comprising a dilated fundus examination, ocular coherence tomography of the macula and nerve fiber layer, and Humphrey visual field testing. Twenty-six patients, with an average age of 13 years (range 2-23 years) and an average follow-up duration of 413 days were included in the analysis. Three different MEKi were used: selumetinib (77%), trametinib (23%), and mirdametinib (4%). None of the patients experienced retinopathy at any point during the study. Some patients had pre-existing optic neuropathies (27%), but no instances of nerve changes occurred after commencing MEKi therapy. Four patients (15%) exhibited symptoms of dry eye, all of which were effectively managed with topical lubrication.

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BACKGROUND: With the recognition that noncancerous cells function as critical regulators of brain tumor growth, we recently demonstrated that neurons drive low-grade glioma initiation and progression. Using mouse models of neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG), we showed that Nf1 mutation induces neuronal hyperexcitability and midkine expression, which activates an immune axis to support tumor growth, such that high-dose lamotrigine treatment reduces Nf1-OPG proliferation. Herein, we execute a series of complementary experiments to address several key knowledge gaps relevant to future clinical translation. METHODS: We leverage a collection of Nf1-mutant mice that spontaneously develop OPGs to alter both germline and retinal neuron-specific midkine expression. Nf1-mutant mice harboring several different NF1 patient-derived germline mutations were employed to evaluate neuronal excitability and midkine expression. Two distinct Nf1-OPG preclinical mouse models were used to assess lamotrigine effects on tumor progression and growth in vivo. RESULTS: We establish that neuronal midkine is both necessary and sufficient for Nf1-OPG growth, demonstrating an obligate relationship between germline Nf1 mutation, neuronal excitability, midkine production, and Nf1-OPG proliferation. We show anti-epileptic drug (lamotrigine) specificity in suppressing neuronal midkine production. Relevant to clinical translation, lamotrigine prevents Nf1-OPG progression and suppresses the growth of existing tumors for months following drug cessation. Importantly, lamotrigine abrogates tumor growth in two Nf1-OPG strains using pediatric epilepsy clinical dosing. CONCLUSIONS: Together, these findings establish midkine and neuronal hyperexcitability as targetable drivers of Nf1-OPG growth and support the use of lamotrigine as a potential chemoprevention or chemotherapy agent for children with NF1-OPG.

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Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines, chemokines) elaboration. Their common pathobiology raises the intriguing possibility that brain injury could create a tissue microenvironment permissive for tumor formation. Leveraging several murine models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome and two experimental methods of brain injury, we demonstrate that both optic nerve crush and diffuse traumatic brain injury induce optic glioma (OPG) formation in mice harboring Nf1-deficient preneoplastic progenitors. We further elucidate the underlying molecular and cellular mechanisms, whereby glutamate released from damaged neurons stimulates IL-1ß release by oligodendrocytes to induce microglia expression of Ccl5, a growth factor critical for Nf1-OPG formation. Interruption of this cellular circuit using glutamate receptor, IL-1ß or Ccl5 inhibitors abrogates injury-induced glioma progression, thus establishing a causative relationship between injury and tumorigenesis.

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In this paper, the authors present a clinical picture of the diagnosis and current treatment regimens of optic pathway glioma in the pediatric population, with an emphasis on the role of an ophthalmic diagnosis in the differentiation and monitoring of lesions. Glioma is the most common optic nerve tumor in children. MATERIAL: Articles in PubMed, Scholar and Website were reviewed, taking into account current standards of management related to sporadic or NF1-related optic glioma, epidemiology, location, course of the disease, clinical manifestations, histological types of the tumor, genetic predisposition, diagnostic ophthalmic tests currently applicable in therapeutic monitoring of the tumor, neurological diagnosis, therapeutic management and prognosis. The importance of current screening recommendations, in line with standards, was emphasized. RESULTS: Glioma occurs in children most often in the first decade of life. Initially, they may be asymptomatic, and clinically ophthalmic changes are associated with the organ of vision or with systemic changes. Gliomas associated with the NF1 mutation have a better prognosis for sporadic gliomas. Diagnosis includes radiological imaging methods/MRI/ophthalmology/OCT and visual acuity log MAR assessment. The basis of treatment is clinical observation. In the case of disease progression, surgical treatment, chemotherapy and targeted therapy are used. CONCLUSION: Further research into novel techniques for detecting gliomas would allow for early monitoring of the disease.

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Optic pathway glioma (OPG) occurs in as many as one-fifth of individuals with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Generally considered low-grade and slow growing, many children with NF1-OPGs remain asymptomatic. However, due to their location within the optic pathway, ~20-30% of those harboring NF1-OPGs will experience symptoms, including progressive vision loss, proptosis, diplopia, and precocious puberty. While treatment with conventional chemotherapy is largely effective at attenuating tumor growth, it is not clear whether there is much long-term recovery of visual function. Additionally, because these tumors predominantly affect young children, there are unique challenges to NF1-OPG diagnosis, monitoring, and longitudinal management. Over the past two decades, the employment of authenticated genetically engineered Nf1-OPG mouse models have provided key insights into the function of the NF1 protein, neurofibromin, as well as the molecular and cellular pathways that contribute to optic gliomagenesis. Findings from these studies have resulted in the identification of new molecular targets whose inhibition blocks murine Nf1-OPG growth in preclinical studies. Some of these promising compounds have now entered into early clinical trials. Future research focused on defining the determinants that underlie optic glioma initiation, expansion, and tumor-induced optic nerve injury will pave the way to personalized risk assessment strategies, improved tumor monitoring, and optimized treatment plans for children with NF1-OPG.

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Introduction: Optic pathway gliomas (OPGs) are associated with significant risk of visual and endocrine morbidity, but data on long-term outcomes in symptomatic patients is sparse. This study reviews the clinical course, disease progression, survival outcomes and long-term sequelae in pediatric patients with symptomatic OPGs in our institution over three decades. Methods: Retrospective review of patients with symptomatic OPG treated in a single tertiary pediatric oncology center from 1984 to 2016. Results: A total of 37 patients were diagnosed with symptomatic OPG. Decreased visual acuity was the commonest presenting symptom (75.7%). Surgical intervention was performed in 62.2%; 56.5% underwent biopsy, 26.1% surgical debulking and 17.4% had orbital decompression with cystic fenestration and cosmetic optic nerve excision at different treatment intervals. CSF diversion was performed in 47.8% patients. Histopathologic examination confirmed 86% to be pilocytic astrocytoma and 1 ganglioglioma. 46% received chemotherapy and 48% had radiotherapy, at different intervals. Median follow-up was 13.74 years. In NF1 patients, overall survival (OS) was 100% at 5 years and 55.6 ± 24.8% at 25 years while progression-free-survival (PFS) was 50 ± 15.8% at 5 and 20 years. In non-NF1 patients, OS was 96.2 ± 3.8% at 5 years and 87.4 ± 9% at 25-years. 5-year PFS was 53.8 ± 9.8% and 25-year PFS was 49.0 ± 10%. Cumulative PFS was 53 ± 8.3% at 5 years and 49.7 ± 8.4% at 20 years while cumulative OS was 97.2 ± 2.7% at 5 years and 77.5 ± 10.8% at 25 years. 59.5% patients developed post-operative endocrinopathy. Long-term vision was normal in 8.1%, improved in 13.5%, stabilized in 40.5% but worsened in 37.8% patients. Three patients treated with radiotherapy developed second brain tumors. Conclusion: 25-year OS in this cohort was 77.5% but survivorship carried significant long-term morbidities including radiation-induced second malignant brain tumors.

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The sphenoid ridge approach (SRA) was initially described as a surgical technique for treating vascular pathologies near the Sylvian fissure. However, limited studies have systematically explored the use of skull base techniques in pediatric patients. This study investigated an extended variation in the sphenoid ridge approach (E-SRA), which systematically removed the pterion, orbital walls (roof and lateral wall), greater sphenoid wing, and anterior clinoid process to access the base of the skull. OBJECTIVE: This report aimed to evaluate the advantages of the extradural removal of the orbital roof, pterion, sphenoid wing, and anterior clinoid process as a complement to the sphenoid ridge approach in pediatric patients. PATIENTS AND METHODS: We enrolled 36 patients with suspected neoplastic diseases in different regions. The E-SRA was performed to treat the patients. Patients were included based on the a priori objective of a biopsy or a total gross resection. The surgical time required to complete the approach, associated bleeding, and any complications were documented. RESULTS: Our results demonstrated that the proposed a priori surgical goal, biopsy, or resection were successfully achieved in all cases. In addition, using the E-SRA technique was associated with a shorter operative time, minimal bleeding, and a lower incidence of complications. The most frequently encountered complications were related to dural closure. CONCLUSIONS: The extended sphenoid ridge approach represents a safe and effective option for managing intracranial tumors in pediatrics.

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Pediatric low-grade gliomas represent the most common childhood brain tumor class. While often curable, some tumors fail to respond and even successful treatments can have life-long side effects. Many clinical trials are underway for pediatric low-grade gliomas. However, these trials are expensive and challenging to organize due to the heterogeneity of patients and subtypes. Advances in sequencing technologies are helping to mitigate this by revealing the molecular landscapes of mutations in pediatric low-grade glioma. Functionalizing these mutations in the form of preclinical models is the next step in both understanding the disease mechanisms as well as for testing therapeutics. However, such models are often more difficult to generate due to their less proliferative nature, and the heterogeneity of tumor microenvironments, cell(s)-of-origin, and genetic alterations. In this review, we discuss the molecular and genetic alterations and the various preclinical models generated for the different types of pediatric low-grade gliomas. We examined the different preclinical models for pediatric low-grade gliomas, summarizing the scientific advances made to the field and therapeutic implications. We also discuss the advantages and limitations of the various models. This review highlights the importance of preclinical models for pediatric low-grade gliomas while noting the challenges and future directions of these models to improve therapeutic outcomes of pediatric low-grade gliomas.

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Background: Surgical treatment of optic nerve tumors is challenging. The study's objective was to evaluate the efficacy of a combined endoscopic transethmoid and transconjunctival approach in patients without functional vision. Design: A retrospective, noncomparative case series. Methods: Retrospective data were collected from all patients who had undergone tumor resection using this approach at the authors' institution between 2015 and 2021. Preoperative assessments included magnetic resonance imaging and ophthalmological examinations, and re-assessments were conducted three months after surgery and regularly during the follow-up period. Results: Seventeen patients, mean age 35 ± 19.0 years, were enrolled. Of these, 64.7% presented with visual acuity (VA) of light perception or no light perception. Gross total resection was realized in all patients. The average decline in exophthalmos was 3.63 ± 1.93 mm. Tumor histopathological analysis identified 12 optic nerve sheath meningiomas and 5 optic gliomas. The mean follow-up time was 30 months during which there was no local recurrence in any of the patients. Conclusions: The combined endoscopic transethmoid and transconjunctival approach offers an additional choice for accessing optic nerve tumors. The procedure is both safe and effective and provides an alternative transcranial route to the orbit.

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BACKGROUND: Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome and is one of the most common genetic diseases. It is therefore a condition encountered by radiologists in clinical routine. Since the variability of the clinical expression is very high and several organ systems are affected, we present a standardized diagnostic approach in this article. METHODS: Evaluation of the literature on neurofibromatosis type 1 in the context of radiological examination methods. RESULTS: In addition to the frequently known changes in the central and peripheral nervous system such as optic gliomas and plexiform neurofibromas, lesions from the orthopedic spectrum and vascular changes must also be included in the radiological diagnosis. CONCLUSIONS: Due to the diversity of the clinical picture of NF1, it is reasonable to define an examination strategy which takes into account the needs of radiological routine and also reliably detects the most frequent and prognostically significant pathologies accompanying this disease. In this article, the current recommendations for diagnosis of neurofibromatosis-associated tumors and skeletal changes are summarized, and examination protocols and time intervals are suggested.

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OBJECTIVE: Optic pathway gliomas (OPGs) constitute approximately 3-5% of childhood intracranial tumors. In this study, the authors presented their experience of using the endoscopic endonasal approach to treat patients with OPG located in the chiasma-hypothalamic region and aimed to use the infrachiasmatic corridor in the endoscopic endonasal approach as an alternative to the transcranial approach in the surgical necessity of OPGs. METHODS: We retrospectively analyzed the data of ten patients diagnosed with OPG histopathologically among 3757 cases who underwent endoscopic endonasal surgery between August 1997 and March 2021 at Kocaeli University Faculty of Medicine Pituitary Research Center and Department of Neurosurgery. Mean follow-up period 48.5 months. During the postoperative follow-up period, 3 of these 10 patients underwent reoperation due to tumor recurrence. Combined (endoscopic endonasal approach + transcranial approach) approach was applied to 2 patients in the same session. Surgical and clinical outcomes were evaluated in detail. RESULTS: Ten patients with a mean patient age of 20.6 ± 11.4 were included in this study. The most common complaint was visual impairment. After surgery, improvement in visual impairment was observed in five patients. No increase in postoperative visual impairment was observed in any of the patients. Postoperative panhypopituitarism was not observed in any of the patients. STR resection was performed in 5 patients and NTR resection in 5 patients. No additional treatment was required during follow-up in 4 of 5 patients who underwent NTR. A total of 6 patients received postoperative radiotherapy treatment. CONCLUSIONS: In gliomas located in the chiasma-hypothalamic region, appropriate patient selection and endoscopic endonasal surgical treatment may contribute to the elimination of symptoms due to the mass effect of the tumor. It may also contribute to keeping the disease under control with targeted adjuvant therapies by clarifying the pathological diagnosis of the lesion.

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BACKGROUND: Optic pathway gliomas are uncommon, accounting for 3-5% of childhood brain tumors, and are mostly classified as pilocytic astrocytomas (PAs). PAs of the optic nerve are particularly rare in adults. OBSERVATIONS: The authors presented the case of PA of the left optic nerve in a 49-year-old woman along with detailed pathological and molecular analyses and sequential magnetic resonance imaging. The tumor had progressed during 5 years of follow-up along with cyst formation and intracystic hemorrhage; it had a thick capsule and contained xanthochromic fluid. The boundary between tumor and optic nerve was unclear. B-type Raf kinase (BRAF) V600E point mutations or translocations, IDH1-R132H mutations, loss of alpha-thalassemia/mental retardation X-linked, and 1p/19q codeletion were negative. LESSONS: BRAF alterations in pediatric PAs of the optic nerve are less frequent than those observed in PAs in other lesions; the same molecular pattern was observed in the adult case, without changes in BRAF. Surgical management should be indicated only in cases with severely impaired vision or disfigurement because there is no clear border between the tumor and optic nerve. Further discussion is needed to optimize the treatment for adult optic pathway gliomas, including radiotherapy, chemotherapy, and molecular-targeted therapies, in addition to surgical intervention.

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Background: Hemorrhage into optic pathway-hypothalamic glioma (OPHG) is rare. Variable clinical presentations and outcomes are associated with such pathology. We aim to present two infants presented with OPHG and a systematic review of the literature. Methods: We describe two cases of infants presenting with sudden decreased vision, poor feeding, and irritability due to OPHG. Both patients underwent urgent craniotomy and subtotal resection followed by chemotherapy. We systematically reviewed the literature using PubMed, Google Scholar, and Embase. In addition, we included all English published reports for all ages discussing the optic pathway (optic nerve and optic chiasm) or hypothalamic glioma associated with hemorrhage from the year of the first reported case (1970) to January 2022. Results: Of 17,949, 44 articles met the inclusion criteria of this review. A total of 56 cases were described with a mean of 21.35 years (0.5-70), with the male gender 52% and the female gender 45%. The hemorrhage location was sellar/suprasellar in 43% cases. Histopathology of included cases was pilocytic astrocytoma in 41%, followed by pilomyxoid astrocytoma in 16% cases. The outcome was unfavorable; 37.5% cases showed improvement, whereas 18% cases resulted in death. Conclusion: Apoplexy of the OPHG can be fatal and associated with poor outcomes. A systematic review of the literature has shown that younger age, pilocytic or pilomexyoid astrocytoma histopathology, and chiasmal/hypothalamic locations are associated with a higher risk of intertumoral hemorrhage and poor prognosis. Further genetic studies for OPHG may provide information for high-risk patients.

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Optic pathway glioma (OPG) is a rare tumor located in optic nerve, optic tract, or optic chiasm. Treatment options for OPG include surgery, radiation therapy (RT), and chemotherapy. Although RT may provide favorable long-term outcomes in manner of either adjuvant or salvage aim, chemotherapy-first approach is increasingly performed due to possible late effects of RT. Proton beam RT may allow normal tissue sparing of radiation exposure compared to conventional X-ray treatment. Therefore, proton beam RT is expected to reduce complications from RT. This review discusses the recent updates on oncologic outcomes of OPG, late toxicities following RT, and compares the outcomes between X-ray treatment and proton beam RT.

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Malignant optic gliomas are an uncommon pathology, with around 67 cases reported worldwide in the literature. We present the case of a 77-year-old-male with a two-month history of progressive vision loss, ultimately leading to bilateral blindness. The initial clinical suspicion was a non-inflammatory ischemic optic neuropathy. Stereotactic biopsy was performed on the optic chiasm, and the histopathological diagnosis was confirmed as Glioblastoma.

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BACKGROUND: Emerging insights from numerous laboratories have revealed important roles for nonneoplastic cells in the development and progression of brain tumors. One of these nonneoplastic cellular constituents, glioma-associated microglia (GAM), represents a unique population of brain monocytes within the tumor microenvironment that have been reported to both promote and inhibit glioma proliferation. To elucidate the role of GAM in the setting of low-grade glioma (LGG), we leveraged RNA sequencing meta-analysis, genetically engineered mouse strains, and human biospecimens. METHODS: Publicly available disease-associated microglia (DAM) RNA-seq datasets were used, followed by immunohistochemistry and RNAScope validation. CD11a-deficient mouse microglia were used for in vitro functional studies, while LGG growth in mice was assessed using anti-CD11a neutralizing antibody treatment of Neurofibromatosis type 1 (Nf1) optic glioma mice in vivo. RESULTS: We identified Itgal/CD11a enrichment in GAM relative to other DAM populations, which was confirmed in several independently generated murine models of Nf1 optic glioma. Moreover, ITGAL/CD11A expression was similarly increased in human LGG (pilocytic astrocytoma) specimens from several different datasets, specifically in microglia from these tumors. Using CD11a-knockout mice, CD11a expression was shown to be critical for murine microglia CX3CL1 receptor (Cx3cr1) expression and CX3CL1-directed motility, as well as glioma mitogen (Ccl5) production. Consistent with an instructive role for CD11a+ microglia in stromal control of LGG growth, antibody-mediated CD11a inhibition reduced mouse Nf1 LGG growth in vivo. CONCLUSIONS: Collectively, these findings establish ITGAL/CD11A as a critical microglia regulator of LGG biology relevant to future stroma-targeted brain tumor treatment strategies.

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OBJECTIVE: To investigate the variant spectrum and genotype-phenotype correlations in a Turkish cohort with Neurofibromatosis Type-1 (NF1). MATERIALS AND METHODS: We retrospectively investigated the clinical and molecular data of 138 NF1 patients from 129 families who had been followed-up for a median of 3.9 (1.25-18.5) years. RESULTS: NF1 sequencing revealed 73 different intragenic variants, 19 of which were novel. Seven large deletions were detected by multiplex ligation-dependent probe amplification (MLPA) analyses. The total detection rate of pathogenic NF1 variants was found to be 87.1%. Comparing age groups, cutaneous neurofibromas, freckling, and Lisch nodules were more prevalent in patients older than 12 years (p > .05). Optic glioma detected in 17.3% of the patients and was significantly more common before the age of 6 (p > .001). Other solid tumors developed in 5% of the patients. There was no genotype-phenotype correlation between patients with truncating and nontruncating variants. However, six out of seven patients with large deletions had significant developmental delay, one patient with the c.2970_2972delAAT (p.Met992del) variant had only typical pigmentary features, and another patient with the c.4267A > G (p.Lys1423Glu) variant had CALMs, freckling, neurofibromas, and Noonan-like phenotype. CONCLUSIONS: We described 19 novel variants and seven large deletions in NF1. Applying MLPA assay in NF1 is useful in expanding the molecular diagnosis. Although very limited genotype-phenotype correlation has been reported in NF1, the fact that specific phenotypic findings were observed in our patients with large deletions and two intragenic variants supports the studies published recently.

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BACKGROUND: Neurofibromatosis type 1 (NF-1) is a neurocutaneous autosomal dominant disorder that predisposes patients to develop intracranial low-grade gliomas (LGGs). Most LGGs in patients with NF-1 involve the optic pathway but can arise anywhere throughout the central nervous system. NF-1-related disseminated pediatric LGG (dPLGG) in the absence of a dominant optic pathway glioma has not been described. OBSERVATIONS: The authors discussed a case of a 10-year-old boy who presented with consideration for biopsy with nonoptic pathway PLGG with craniospinal dPLGG in the setting of NF-1. The patient's primary lesion, located in the right medulla, was initially treated with surveillance before induction chemotherapy with carboplatin and vincristine was initiated. However, surveillance imaging demonstrated significant increase in size and enhancement, and subsequent craniospinal imaging demonstrated extensive nodular dissemination in the cervicothoracic spine. A biopsy and molecular testing were subsequently performed to further evaluate the tumor, and the patient was diagnosed with dPLGG with CDKN2A deletion. LESSONS: Thorough craniospinal magnetic resonance imaging evaluation and biopsy in nonoptic pathway-dominant brain lesions in NF-1 are warranted in patients with atypical clinical and radiological findings in whom standard chemotherapeutic therapy fails.

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Optic nerve glioma (ONG) is a rare, typically slow-growing WHO I grade tumor that affects the visual pathways. ONG is most commonly seen in the pediatric population, in association with neurofibromatosis type 1 syndrome. However, sporadic adult cases may also occur and may clinically behave more aggressively, despite benign histopathology. Genetic characterization of these tumors, particularly in the adult population, is lacking. A 39-year-old female presented with 1 month of progressive left-sided visual loss secondary to a enhancing mass along the left optic nerve sheath. Initial empiric management with focal radiotherapy failed to prevent tumor progression, prompting open biopsy which revealed a WHO I pilocytic astrocytoma of the optic nerve. Whole-exome sequencing of the biopsy specimen revealed somatic mutations in NF1,FGFR1 and PTPN11 that may provide actionable targets for molecularly guided therapies. Genetic characterization of ONG is lacking but is needed to guide the management of these rare but complex tumors. The genomic alterations reported in this case contributes to understanding the pathophysiology of adult sporadic ONG and may help guide future clinical prognostication and development of targeted therapies.

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