Associations between brain network, puberty, and behaviors in boys with Klinefelter syndrome

doi:10.1007/s00787-024-02501-y

Observational Study

. 2025 Feb;34(2):585-597.

doi: 10.1007/s00787-024-02501-y. Epub 2024 Jun 21.

Associations between brain network, puberty, and behaviors in boys with Klinefelter syndrome

Rihui Li^{1

2}, Lara C Foland-Ross³, Tracy Jordan³, Matthew J Marzelli³, Judith L Ross^{4

5}, Allan L Reiss^{3

6

7}

Affiliations

¹ Center for Cognitive and Brain Sciences, Institute of Collaborative Innovation, University of Macau, Taipa, Macao S.A.R., China. rihuili@um.edu.mo.
² Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 74305, USA. rihuili@um.edu.mo.
³ Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 74305, USA.
⁴ Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
⁵ Nemours duPont Hospital for Children, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
⁶ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 74305, USA.
⁷ Department of Radiology, Stanford University School of Medicine, Stanford, CA, 74305, USA.

PMID: 38904702
PMCID: PMC11662083 (available on 2025-08-01)
DOI: 10.1007/s00787-024-02501-y

Observational Study

Associations between brain network, puberty, and behaviors in boys with Klinefelter syndrome

Rihui Li et al. Eur Child Adolesc Psychiatry. 2025 Feb.

. 2025 Feb;34(2):585-597.

doi: 10.1007/s00787-024-02501-y. Epub 2024 Jun 21.

Authors

Rihui Li^{1

2}, Lara C Foland-Ross³, Tracy Jordan³, Matthew J Marzelli³, Judith L Ross^{4

5}, Allan L Reiss^{3

6

7}

Affiliations

¹ Center for Cognitive and Brain Sciences, Institute of Collaborative Innovation, University of Macau, Taipa, Macao S.A.R., China. rihuili@um.edu.mo.
² Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 74305, USA. rihuili@um.edu.mo.
³ Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 74305, USA.
⁴ Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
⁵ Nemours duPont Hospital for Children, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
⁶ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 74305, USA.
⁷ Department of Radiology, Stanford University School of Medicine, Stanford, CA, 74305, USA.

PMID: 38904702
PMCID: PMC11662083 (available on 2025-08-01)
DOI: 10.1007/s00787-024-02501-y

Abstract

Background: Klinefelter syndrome (KS), also referred to as XXY syndrome, is a significant but inadequately studied risk factor for neuropsychiatric disability. Whether alterations in functional brain connectivity or pubertal delays are associated with aberrant cognitive-behavioral outcomes in individuals with KS is largely unknown. In this observational study, we investigated KS-related alterations in the resting-state brain network, testosterone level, and cognitive-behavioral impairment in adolescents with Klinefelter syndrome.

Methods: We recruited 46 boys with KS, ages 8 to 17 years, and 51 age-matched typically developing (TD) boys. All participants underwent resting-state functional magnetic resonance imaging scans, pubertal, and cognitive-behavioral assessments. Resting-state functional connectivity and regional brain activity of the participants were assessed.

Results: We found widespread alterations in global functional connectivity among the inferior frontal gyrus, temporal-parietal area, and hippocampus in boys with KS. Aberrant regional activities, including enhanced fALFF in the motor area and reduced ReHo in the caudate, were also found in the KS group compared to the TD children. Further, using machine learning methods, brain network alterations in these regions accurately differentiated boys with KS from TD controls. Finally, we showed that the alterations of brain network properties not only effectively predict cognitive-behavioral impairment in boys with KS, but also appear to mediate the association between total testosterone level and language ability, a cognitive domain at particular risk for dysfunction in this condition.

Conclusion: Our results offer an informatic neurobiological foundation for understanding cognitive-behavioral impairments in individuals with KS and contribute to our understanding of the interplay between pubertal status, brain function, and cognitive-behavioral outcome in this population.

Keywords: Cognitive-behavioral impairment; Klinefelter syndrome; Puberty; Resting-state functional connectivity; Testosterone level; Verbal skill.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests.

References

1. Smyth CM and Bremner WJ, “Klinefelter syndrome,” Arch Intern Med, vol. 158, no. 12, pp. 1309–14, Jun 22 1998, doi: 10.1001/archinte.158.12.1309. - DOI - PubMed
1. Samango-Sprouse CA, Counts DR, Tran SL, Lasutschinkow PC, Porter GF, and Gropman AL, “Update On The Clinical Perspectives And Care Of The Child With 47,XXY (Klinefelter Syndrome),” Appl Clin Genet, vol. 12, pp. 191–202, 2019, doi: 10.2147/TACG.S180450. - DOI - PMC - PubMed
1. Klinefelter HF, Reifenstein ECJ, and Albright F, “Syndrome Characterized by Gynecomastia, Aspermatogenesis without A-Leydigism, and Increased Excretion of Follicle-Stimulating Hormone1,” The Journal of Clinical Endocrinology and Metabolism, vol. 2, pp. 615–627, 1942.
1. Skakkebaek A, Gravholt CH, Chang S, Moore PJ, and Wallentin M, “Psychological functioning, brain morphology, and functional neuroimaging in Klinefelter syndrome,” Am J Med Genet C Semin Med Genet, vol. 184, no. 2, pp. 506–517, Jun 2020, doi: 10.1002/ajmg.c.31806. - DOI - PubMed
1. Tartaglia N, Cordeiro L, Howell S, Wilson R, and Janusz J, “The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome),” Pediatr Endocrinol Rev, vol. 8 Suppl 1, no. 0 1, pp. 151–9, Dec 2010. [Online]. Available: https://www.ncbi.nlm.nih.gov/pubmed/21217607. - PMC - PubMed

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[1] Smyth CM and Bremner WJ, “Klinefelter syndrome,” Arch Intern Med, vol. 158, no. 12, pp. 1309–14, Jun 22 1998, doi: 10.1001/archinte.158.12.1309. - DOI - PubMed

[2] Smyth CM and Bremner WJ, “Klinefelter syndrome,” Arch Intern Med, vol. 158, no. 12, pp. 1309–14, Jun 22 1998, doi: 10.1001/archinte.158.12.1309. - DOI - PubMed

[3] Samango-Sprouse CA, Counts DR, Tran SL, Lasutschinkow PC, Porter GF, and Gropman AL, “Update On The Clinical Perspectives And Care Of The Child With 47,XXY (Klinefelter Syndrome),” Appl Clin Genet, vol. 12, pp. 191–202, 2019, doi: 10.2147/TACG.S180450. - DOI - PMC - PubMed

[4] Samango-Sprouse CA, Counts DR, Tran SL, Lasutschinkow PC, Porter GF, and Gropman AL, “Update On The Clinical Perspectives And Care Of The Child With 47,XXY (Klinefelter Syndrome),” Appl Clin Genet, vol. 12, pp. 191–202, 2019, doi: 10.2147/TACG.S180450. - DOI - PMC - PubMed

[5] Klinefelter HF, Reifenstein ECJ, and Albright F, “Syndrome Characterized by Gynecomastia, Aspermatogenesis without A-Leydigism, and Increased Excretion of Follicle-Stimulating Hormone1,” The Journal of Clinical Endocrinology and Metabolism, vol. 2, pp. 615–627, 1942.

[6] Klinefelter HF, Reifenstein ECJ, and Albright F, “Syndrome Characterized by Gynecomastia, Aspermatogenesis without A-Leydigism, and Increased Excretion of Follicle-Stimulating Hormone1,” The Journal of Clinical Endocrinology and Metabolism, vol. 2, pp. 615–627, 1942.

[7] Skakkebaek A, Gravholt CH, Chang S, Moore PJ, and Wallentin M, “Psychological functioning, brain morphology, and functional neuroimaging in Klinefelter syndrome,” Am J Med Genet C Semin Med Genet, vol. 184, no. 2, pp. 506–517, Jun 2020, doi: 10.1002/ajmg.c.31806. - DOI - PubMed

[8] Skakkebaek A, Gravholt CH, Chang S, Moore PJ, and Wallentin M, “Psychological functioning, brain morphology, and functional neuroimaging in Klinefelter syndrome,” Am J Med Genet C Semin Med Genet, vol. 184, no. 2, pp. 506–517, Jun 2020, doi: 10.1002/ajmg.c.31806. - DOI - PubMed

[9] Tartaglia N, Cordeiro L, Howell S, Wilson R, and Janusz J, “The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome),” Pediatr Endocrinol Rev, vol. 8 Suppl 1, no. 0 1, pp. 151–9, Dec 2010. [Online]. Available: https://www.ncbi.nlm.nih.gov/pubmed/21217607. - PMC - PubMed

[10] Tartaglia N, Cordeiro L, Howell S, Wilson R, and Janusz J, “The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome),” Pediatr Endocrinol Rev, vol. 8 Suppl 1, no. 0 1, pp. 151–9, Dec 2010. [Online]. Available: https://www.ncbi.nlm.nih.gov/pubmed/21217607. - PMC - PubMed

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Associations between brain network, puberty, and behaviors in boys with Klinefelter syndrome

Affiliations

Associations between brain network, puberty, and behaviors in boys with Klinefelter syndrome

Authors

Affiliations

Abstract

Conflict of interest statement

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Abstract

Conflict of interest statement

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