Looking at Optic Nerve Sheath Meningiomas Through Genetics-From Clinic to Bench and Back Again

Optic nerve sheath meningiomas (ONSMs) occupy a unique intersection between neuro-oncology and genetics. Although most cases arise in middle-aged women as solitary, slow-growing tumors, pediatric onset, bilateral disease, or rapid progression frequently signal an underlying germline alteration, most often in neurofibromatosis type II (NF2). This narrative review synthesizes the literature through May 2025, examining clinical behavior, imaging, pathology, hereditary syndromes, and the molecular drivers of ONSMs, with particular emphasis on NF2, SMARCB1, TRAF7, and recent copy-number and methylation studies. Classic sporadic ONSMs seldom exhibit loss of chromosome 22q. However, somatic NF2 alterations and occasional changes in chromatin-remodeling genes still converge on Hippo pathway output (Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ)-driven transcriptional activity), phosphoinositide 3-kinase-protein kinase B (PI3K-AKT), and MAPK signaling. Emerging multi-omics data indicate that optic nerve tumors represent a molecularly distinct subset within the meningioma spectrum. This finding may explain the associated characteristically indolent growth and favorable response to conformal radiotherapy. Genotyping refines risk stratification: early NF2 testing is warranted in children and in bilateral or atypical presentations, enabling timely surveillance and genetic counseling. While fractionated stereotactic radiotherapy remains the mainstay of therapy, pathway-targeted and gene-replacement strategies developed for NF2-associated tumors may soon expand therapeutic options. Given the site-specific diagnostic and functional constraints of peri-optic tumors, larger collaborative cohorts and genotype-guided trials are essential to translate these biological insights into precision care for patients with ONSMs.