Optic Nerve Sheath Meningioma Genetics Reveal Distinct Molecular Subsets and Guide Precision Care

Optic nerve sheath meningiomas (ONSMs) are rare tumors at the intersection of neuro-oncology and genetics. While often solitary and slow-growing in middle-aged women, pediatric onset, bilateral disease, or rapid progression frequently indicate underlying germline alterations, predominantly in neurofibromatosis type II (NF2). Current understanding of their specific molecular drivers and how these influence clinical behavior remains incomplete, limiting precision in risk stratification and targeted therapeutic development beyond standard radiotherapy. This review addresses the need to synthesize emerging genetic insights to guide clinical practice.

This narrative review synthesized literature through May 2025, comprehensively examining the clinical behavior, imaging characteristics, pathology, hereditary syndromes, and molecular drivers of ONSMs. A particular emphasis was placed on identifying key genetic alterations, including NF2, SMARCB1, and TRAF7, as well as insights from recent copy-number and methylation studies. The authors aimed to integrate these findings to understand the molecular landscape of ONSMs and their implications for diagnosis and treatment.

The review revealed that classic sporadic ONSMs seldom exhibit loss of chromosome 22q, a common feature in other meningioma types. However, somatic NF2 alterations and occasional changes in chromatin-remodeling genes like SMARCB1 and TRAF7 consistently converge on critical signaling pathways. These include Hippo pathway output (YAP/TAZ-driven transcriptional activity), phosphoinositide 3-kinase-protein kinase B (PI3K-AKT), and MAPK signaling. Emerging multi-omics data strongly indicate that optic nerve tumors represent a molecularly distinct subset within the broader meningioma spectrum. This distinction may explain their 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, pathway-targeted and gene-replacement strategies developed for NF2-associated tumors may soon expand therapeutic options.