ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This clinical cross-sectional study provides new data on the neurodevelopmental aspects of Klinefelter syndrome (KS). It investigated the brain activation patterns in 43 adolescent males with KS (mean age 12.3±2.3 years) compared to an age-matched typically-developing (n=41) control group during the go/no-go task, an executive function assessment. Behavioral assessment tests, and functional magnetic resonance imaging (fMRI) were used.

Adolescents with KS showed reduced task accuracy and lower activation in brain regions involved in executive function, such as the right inferior frontal gyrus, anterior insula, striatum, and dorsal anterior cingulate gyrus. In the KS group, reduced activation in the paracingulate and dorsal anterior cingulate cortex was linked to lower testosterone levels and smaller testes volume, suggesting a relationship between pubertal development and brain function. Parent-reported executive dysfunction also correlated with lower testes volume but go/no go task performance did not.

These findings indicate a neural basis for executive dysfunction in KS, in which altered pubertal development and testosterone deficiency may play a role, although the study design does not allow causal inference. Reduced testicular volume and reduced brain activation might also both be signs of a more severe phenotype overall.

Future studies should further explore whether executive dysfunction in KS can be partially reversed with testosterone replacement therapy (TRT) and whether the timing of TRT initiation affects outcomes.