# Brain and Behavior during Puberty in Klinefelter Syndrome.

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $331,065

## Abstract

Klinefelter syndrome (KS) is a highly prevalent sex chromosome aneuploidy that is characterized by an
increased number of X chromosomes (47,XXY) in phenotypic males. Despite its frequent occurrence (up to 1 in
500 male births), clinicians often have little awareness about the diagnosis or management of cognitive-behavioral
and social-emotional symptoms of KS, which can include impairments in language-based learning, deficits in
executive functioning and social skills, and increased symptoms of depression and anxiety. Parents of children
with KS often report greater concerns about these behavioral disturbances relative to commonly observed
physical features in KS (e.g., tall stature and testicular failure), since they have the potential to affect everyday
function at home and at school, and can negatively influence long term social and vocational outcomes.
 Most males with KS first experience testicular failure (i.e., deficiency in testosterone and/or hypogonadal
symptoms) starting in mid-puberty. For this reason, pediatric endocrinologists typically prescribe testosterone
replacement therapy (TRT) starting around this time. However, there remain large gaps in knowledge and
fundamental questions about the effects of this treatment on neural and behavioral development in males with KS,
despite well-documented effects of testosterone on the brain and cognition in typically developing males.
 The prospective, longitudinal, multi-time point research proposed here would be the first to assess the
effects of TRT, or lack thereof (i.e., testicular failure) on the development of the brain and behavior in adolescents
with KS using multiple levels of analysis (cognitive-behavioral and social-emotional functioning, multi-modal
imaging, pubertal status, hormone levels). Seventy boys with KS and a comparison group of 58 age- and IQ-
matched neurotypical boys between the ages of 8 and 17 years will be recruited and followed annually for up to
three years. Three specific aims will be addressed: (1) to examine the effects of TRT on executive function and
social-emotional symptoms in KS (2) to evaluate the effects of TRT on brain structure and function in KS and, (3)
to elucidate brain-behavior associations in KS (exploratory). We will also examine associations between the
severity testicular failure and brain and behavioral measures.
 The multidisciplinary research we propose offers a first-of-its-kind opportunity to provide an increased
understanding of how TRT exerts its beneficial effect on cognition, behavior and mood in boys with KS during
the peripubertal period. The results of this study are intended to lead to the development of improved clinical
management of cognitive-behavioral and social-emotional symptoms in boys with KS while advancing our
general knowledge of neural changes underlying cognition, behavior and mood during male puberty.

## Key facts

- **NIH application ID:** 10658503
- **Project number:** 3R01HD092847-05S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Allan L Reiss
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $331,065
- **Award type:** 3
- **Project period:** 2018-08-17 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10658503

## Citation

> US National Institutes of Health, RePORTER application 10658503, Brain and Behavior during Puberty in Klinefelter Syndrome. (3R01HD092847-05S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10658503. Licensed CC0.

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