Context: Executive dysfunction is a well-recognized component of the cognitive phenotype of Klinefelter syndrome (KS), yet the neural basis of KS-associated cognitive weaknesses, and their association with testicular failure is unknown.

Objective: We investigated executive function, brain activation, and pubertal development in adolescents with and without KS.

Methods: Forty-three adolescents with KS (mean age 12.3 ± 2.3 years) and 41 typically developing boys (mean age 11.9 ± 1.8 years) underwent pubertal evaluation, behavioral assessment, and completed functional magnetic resonance imaging (fMRI) as they performed an executive function task, the go/no-go task. Group differences in activation were examined. Associations among activation, executive function, and pubertal development measures were tested in secondary analyses.

Results: Boys with KS exhibited reduced executive function, as well as lower activation in brain regions subserving executive function, including the inferior frontal gyrus, anterior insula, dorsal anterior cingulate cortex, and caudate nucleus. Secondary analyses indicated that the magnitude of activation differences in boys with KS was associated with severity of pubertal developmental delay, as indexed by lower testosterone (t(36) = 2.285; P = .028) and lower testes volume (t(36) = 2.238; P = .031). Greater parent-reported attention difficulties were additionally associated with lower testicular volume (t(36) = -2.028; P = .050).

Conclusion: These findings indicate a neural basis for executive dysfunction in KS and suggest alterations in pubertal development may contribute to increased severity of this cognitive weakness. Future studies that examine whether these patterns change with testosterone replacement therapy are warranted.