Severe Chemoradiotherapy Toxicity in a Pediatric Patient with Leigh Syndrome and Grade IV Isocitrate Dehydrogenase-Mutant Astrocytoma: A Case Report.

BACKGROUND Leigh syndrome is a mitochondrial disorder that results in disruption of oxidative phosphorylation, leading to spongiform lesions throughout the brain, brainstem, and spinal cord. Grade 4 isocitrate dehydrogenase (IDH)-mutant astrocytomas are rare high-grade gliomas; however, IDH-mutant gliomas have relatively high survival rates and sensitivity to chemoradiotherapy. The Warburg effect involves gliomas switching from oxidative to glycolytic pathways. Damage to oxidative pathways caused by Leigh syndrome could lead to premature shifting to glycolytic pathways, in which case patients with mitochondrial disorders may have increased susceptibility to glioma progression. Additionally, chemotherapy and radiation therapy lead to mitochondrial dysfunction and the production of reactive oxygen species, which increases toxicity when these patients receive chemoradiotherapy for cancer treatment. CASE REPORT A 10-year-old boy with Leigh syndrome was diagnosed with a WHO grade 4 IDH-mutant anaplastic astrocytoma and received chemoradiotherapy. The patient experienced severe toxicity to the chemoradiotherapy, manifesting as refractory grade IV thrombocytopenia. Upon presentation to the emergency department for epistaxis and desaturations, the patient's clinical course rapidly declined. The patient developed hypovolemic shock, alveolar hemorrhage, acute respiratory distress syndrome, breakthrough seizures, central apnea, neutropenia, tumor recurrence, and possible radiation necrosis. Following loss of brainstem function, the patient was compassionately extubated. CONCLUSIONS This is the first reported case of both Leigh syndrome and an IDH-mutant astrocytoma in a pediatric patient. The patient's unusual clinical course is likely due to the relationship between mitochondrial dysfunction, IDH-mutant gliomas, and toxic sensitivity to chemoradiotherapy. This case highlights the need for caution in formulating treatment plans for similar patient cases in the future.