Neuropathology division faculty and fellows have reviewed how Neurofibromatosis 1 (NF1) affects the brain in a recent paper published in Acta Neuropathologica. NF1 is a common autosomal dominant genetic disorder. Patients with NF1 are at increased risk for central nervous system (CNS) manifestations including structural, functional, and neoplastic diseases. A variety of non-neoplastic structural (macrocephaly, hydrocephalus, aqueductal stenosis, and vasculopathy) and functional (epilepsy, impaired cognition, attention deficits, and autism spectrum disorder) abnormalities occur with variable frequency in individuals with NF1. In addition, there is increasing evidence that CNS neoplasms in people with the NF1 syndrome are due to distinct oncogenic pathways, even when they appear similar to those in non-NF1 patients. A subset of low-grade
astrocytomas in these patients remain difficult to classify using standard criteria, and occasionally demonstrate morphologic features resembling subependymal giant cell astrocytomas that afflict patients with tuberous sclerosis complex (“SEGA-like astrocytomas”). There is also emerging evidence that NF1-associated high-grade astrocytomas have frequent co-existing alterations such as ATRX mutations and an alternative lengthening of telomeres (ALT) phenotype responsible for unique biologic properties. Ongoing efforts are seeking to improve diagnostic accuracy for CNS neoplasms in the setting of NF1 versus
sporadic tumors. In addition, MEK inhibitors, which act on the RAS/MAPK pathway, continue to be studied as rational targets for the treatment of NF1-associated tumors, including CNS tumors.