Longitudinal neuroimaging investigation of fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, provides an opportunity to study the influence of a specific genetic factor on neurodevelopment in the living human brain. We examined voxel-wise gray and white matter volumes (GMV, WMV) over a 2-year period in 1-to 3-year-old boys with FXS (n = 41) and compared these findings to age-and developmentally matched controls (n = 28). We found enlarged GMV in the caudate, thalamus, and fusiform gyri and reduced GMV in the cerebellar vermis in FXS at both timepoints, suggesting early, possibly prenatal, genetically mediated alterations in neurodevelopment. In contrast, regions in which initial GMV was similar, followed by an altered growth trajectory leading to increased size in FXS, such as the orbital gyri, basal forebrain, and thalamus, suggests delayed or otherwise disrupted synaptic pruning occurring postnatally. WMV of striatal-prefrontal regions was greater in FXS compared with controls, and group differences became more exaggerated over time, indicating the possibility that such WM abnormalities are the result of primary FMRP-deficiency-related axonal pathology, as opposed to secondary connectional dysregulation between morphologically atypical brain structures. Our results indicate that structural abnormalities of different brain regions in FXS evolve differently over time reflecting time-dependent effects of FMRP deficiency and provide insight into their neuropathologic underpinnings. The creation of an early and accurate human brain phenotype for FXS in humans will significantly improve our capability to detect whether new disease-specific treatments can "rescue" the FXS phenotype in affected individuals.F ragile X syndrome (FXS) is the most common cause of inherited intellectual disability. The condition is caused by expansion of the CGG repeat in the 5′-untranslated region of the fragile X mental retardation 1 (FMR1) gene, resulting in hypermethylation, transcriptional silencing, and reduction or loss of the gene product, the fragile X mental retardation protein (FMRP) (1). Loss of FMRP disrupts dendritic maturation, synaptic plasticity, and cerebral development (2). Although much is understood about the typical pattern of cerebral abnormality in adults and older children with FXS, relatively little is known about the evolving nature of these abnormalities in early childhood. One of the most consistent observations in FXS is enlargement of the caudate nucleus, which has been noted in children as young as 18 months (3), relative to both typically developing children and those with idiopathic developmental delay (4). Increased caudate size also shows a negative correlation with FMRP, indicating a genetic dose-response relationship (4, 5). Another consistent finding is reduced size of the cerebellar vermis, which has been observed in FXS across a wide range of ages (4-7). Vermis size has been shown to be positively correlated with FMRP (5), although in our recent study w...