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. 2025 Jan:346:111929.
doi: 10.1016/j.pscychresns.2024.111929. Epub 2024 Nov 28.

Neuroanatomical alterations in young boys and adolescents with Klinefelter syndrome

Lara C Foland-Ross  1 , Tracy L Jordan  2 , Matthew J Marzelli  2 , Judith L Ross  3 , Allan L Reiss  4
Affiliations

Neuroanatomical alterations in young boys and adolescents with Klinefelter syndrome

Lara C Foland-Ross et al. Psychiatry Res Neuroimaging. 2025 Jan.

Abstract

Klinefelter syndrome (KS, 47,XXY) is a common sex chromosome aneuploidy in males that is characterized by pubertal developmental delays and a wide range of alterations in cognitive, social and emotional functioning. The neural bases of these behavioral symptoms, however, are unclear. A total of 130 boys and adolescents, including 67 males with KS (11.5 ± 2.8 years) and 63 typically developing (TD; control) males (10.6 ± 2.8 years) underwent MRI scanning and pubertal assessment. Group differences in regional gray matter volume was examined using voxel-based morphometry while controlling for age at scan and total gray matter volume. Thresholded statistical significance maps indicated widespread reductions in frontal and temporal and cerebellar gray matter in males with KS relative to TD males, as well as increases in parietal and occipital gray matter. Secondary analyses explored potential associations between GMV in these regions and pubertal development. Lower testicular volume was a significant predictor of reduced GMV in frontal, temporal and cerebellar subregions, even after accounting for group status (KS, TD). Taken together, these findings add support for a neuroanatomical phenotype of KS and provide initial evidence for a role of pubertal development in KS-associated differences in gray matter structure. Future studies that examine the influence of testosterone supplementation on GMV in males with KS are warranted.

Keywords: Adolescent neurodevelopment; Brain; Gray matter; Klinefelter syndrome; Puberty.

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Conflict of interest statement

Declaration of competing interest All authors have no conflicts of interest to declare.

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