A hierarchical gene-hormone model of cognitive circuit development in Turner syndrome (45,X)

Sex-chromosome dosage and pubertal hormone exposure exert powerful but temporally distinct influences on human brain development, yet their interaction has rarely been formalized within a unified mechanistic framework. Variation in X-chromosome dosage provides a unique opportunity to dissociate early organizational constraints from later modulatory processes shaping cognitive circuits. Here, we synthesize genetic, neuroimaging, neuroendocrine, and neuropsychological evidence to propose a hierarchical gene-hormone-circuit framework of cognitive development. Using Turner syndrome as a biologically constrained model system, we argue that haploinsufficiency of X-linked genes escaping inactivation imposes early, front-loaded constraints on cortical patterning and parietal-frontoparietal connectivity, establishing a neural scaffold that persists across development. Pubertal estrogen signaling subsequently acts as a modulatory influence, refining prefrontal and fronto-limbic circuits that retain plasticity into adolescence, but operating within the limits imposed by earlier gene-dosage-defined architecture. Importantly, this framework departs from prior models by explicitly distinguishing organizational constraints from modulatory influences across developmental timescales. The interaction of these processes yields a domain-specific neurobehavioral organization characterized by persistent visuospatial and executive vulnerabilities alongside variable socio-emotional outcomes. By explicitly integrating sex-chromosome dosage effects with hormone-dependent circuit tuning, this framework advances a generalizable model of hierarchical constraint and modulation in brain development, offering mechanistic insight into sex-linked variation in cognitive and affective circuit maturation and generating testable predictions for future longitudinal neurogenetic and neuroimaging studies.