Klinefelter syndrome (KS) is a highly prevalent sex chromosome aneuploidy syndrome 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 relatively little awareness about diagnosis or management of cognitive-behavioral and social-emotional problems in boys with KS. These problems can include significant language-based learning disability, executive function deficits and ADHD symptoms, impaired social skills, depression and anxiety. Parents of children with KS often report greater concerns about these brain-based disturbances relative to commonly observed physical symptoms in KS such as tall stature and testicular failure, since they have the potential to affect everyday function at home and school, and long- term social and vocational outcome. Most boys with KS experience testicular insufficiency (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 in the pubertal period. However, there remain large gaps in knowledge and fundamental questions about the effects of TRT on brain development and function in KS. Indeed, a wide body of literature indicates that the rise in testosterone at puberty in typically developing boys influences a wave of neural remodeling, and that these changes in neural circuitry are tightly coupled with changes in cognition, behavior and mood. The prospective, longitudinal, multi-time point research proposed here would be the first to assess the effects of TRT on brain development and function in adolescents with KS using multiple levels of analysis (cognitive-behavioral and social-emotional functioning, multi-modal imaging, pubertal status, hormone levels). Sixty boys with KS and a comparison group of 60 age- and IQ-matched neurotypical boys between the ages of 9 and 13 years will be recruited and followed annually for up to four 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 severity of testicular insufficiency as a modifier of brain and behavioral measures in secondary analyses. 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.

Klinefelter syndrome (KS) is a very common genetic condition (extra X chromosome, 47XXY) that occurs only in boys. Clinical problems in boys with KS often include language-based learning disability, executive function deficits and ADHD symptoms, diminished social skills, depression and anxiety, as well as impaired development of puberty associated with testosterone deficiency. The study proposed here would be the first-of- its-kind to comprehensively assess how testosterone replacement therapy affects brain development and function in boys with KS during puberty, with the explicit goal of developing new knowledge that can be used to improve clinical outcomes. The results of the study will also advance our general knowledge of brain changes underlying cognitive-behavioral and social-emotional function during male puberty.