Predictable temporal and spatial patterns of synaptophysin expression previously were demonstrated in the normally developing fetal cerebral cortex, reflecting synaptogenesis without regard to neurotransmitters. We studied 6 human fetal brains with holoprosencephaly in the mid-2nd and 3rd trimesters with immunocytochemical antibodies against synaptophysin and other markers of neuronal maturation. We found not only abnormal patchy patterns of synaptic vesicle reactivity within the disorganized cortical plate, but also loss of precise timing of genetically programmed synaptogenesis. Precociousness in synaptophysin reactivity relative to age-matched controls was demonstrated in 5 cases, and delayed reactivity in 1. Abnormalities were more severe in paramedian than in more lateral regions of the cerebral cortex, following a medio-lateral gradient in the horizontal axis. Extrapial heterotopia exhibited early synaptogenesis. The nodular histological architecture of paramedian zones of cortex contains randomly oriented branching micro-columns of neurones, a unique feature. The hippocampus and subcortical structures did not show precocious synapses, except for delay in the case of cortical synaptic delay. We conclude that synaptic precociousness occurs often in holoprosencephaly but is limited to the cerebral cortex; synaptic delay occurs in others. Precociousness may limit synaptic plasticity and contribute to earlier epileptogenic circuitry. Faulty genetic programming alters not only cortical histological architecture but also the timing of onset of synapse formation.