When sex matters early: clues from pediatric onset multiple sclerosis

INTRODUCTION: Pediatric-onset multiple sclerosis (POMS) provides a unique developmental model to investigate when sex differences first emerge in multiple sclerosis (MS). As disease onset occurs during immune, endocrine, and neural maturation, POMS offers an opportunity to understand how puberty may shape disease susceptibility and subsequent trajectories. AREAS COVERED: This review synthesizes evidence from epidemiological, clinical, neuroimaging, biomarker, and therapeutic studies across prepubertal, peripubertal, and post-pubertal stages. Articles published between 2000 and 2025 were identified through a PubMed/MEDLINE search using terms related to POMS, sex differences, and puberty. Available data indicate that the transition from childhood to adolescence coincides with the emergence of female predominance and sex-dependent patterns of tissue injury. MRI, retinal imaging, and fluid biomarkers suggest that differences in neuroaxonal vulnerability may be detectable early in the disease course. However, most studies remain sex-agnostic. EXPERT OPINION: Sexual dimorphism in MS may emerge earlier than previously recognized, with puberty representing a critical window in which sex-related biological changes begin to shape disease susceptibility and expression. Incorporating sex and pubertal stage into longitudinal POMS research may help elucidate the mechanisms driving these differences, refine early risk stratification, and ultimately support more individualized therapeutic strategies across the MS lifespan.