ID #700 NTRK2-Altered Pilocytic Astrocytoma in a patient with Von Hippel-Lindau Syndrome
Clayton Long, Shea Gallus, Ahmed Gilani, David Shafron, Ross MangumAbstract
Background
Von Hippel–Lindau (VHL) disease is a rare autosomal dominant tumor predisposition disorder caused by pathogenic germline variants in the VHL gene. Individuals with VHL are at increased risk for central nervous system hemangioblastomas, retinal angiomas, renal cell carcinoma, and other neoplasms. Pilocytic astrocytomas represent the most common type of pediatric low-grade glioma and are typically associated with fusions or mutations in the BRAF gene, though other oncogenic drivers such as FGFR, MYB,and NTRK have been identified. The coexistence of VHL syndrome and pilocytic astrocytoma is exceedingly rare.
Case Presentation
We report the case of a two-year-old male with known VHL who presented with progressive peripheral vision loss and nystagmus. Neuroimaging revealed an expansile mass involving the optic chiasm and hypothalamus. Comprehensive histo-molecular characterization, including targeted next-generation sequencing and methylation profiling, resulted in an integrated diagnosis of pilocytic astrocytoma harboring a KCTD16::NTRK2 fusion. The tumor was negative for BRAF alterations or any high-grade features. He has responded favorably both radiographically and ophthalmologically to targeted therapy with the TRK inhibitor, Larotrectinib.
Discussion
To our knowledge, there is only one other documented case of concurrent VHL and low-grade glioma. This finding expands the molecular spectrum of VHL-associated central nervous system tumors and highlights the importance of broad molecular profiling, even in tumors with classic histology and/or known cancer predisposition. Identification of an NTRK fusion is clinically significant, as it introduces the potential role of targeted TRK inhibitor therapy, particularly in cases of inoperable tumors or in the setting of tumor progression or recurrence.
Conclusion
This case underscores the complexity of tumor biology in hereditary cancer predisposition syndromes and supports the integration of molecular diagnostics into the evaluation of pediatric brain tumors. Recognition of actionable alterations such as NTRK fusions may inform precision treatment strategies and improve patient outcomes.