Brain and Behavior during Puberty in Klinefelter Syndrome

Klinefelter综合征(KS)是一种高度流行的性染色体非整倍体综合征，即 以表型男性的X染色体(47，XXY)数目增加为特征的。尽管它经常 发生(高达500名男婴中有1名)，临床医生通常对诊断或 KS男童认知行为和社会情绪问题的处理。这些问题可能 包括严重基于语言的学习障碍、执行功能缺陷和ADHD症状， 社交技能受损，抑郁和焦虑。患有KS的儿童的父母报告说，他们更担心 这些基于大脑的障碍与KS中常见的身体症状有关，如身材高大 和睾丸衰竭，因为它们有可能影响家庭和学校的日常功能，而且长期- 术语社会和职业成果。 大多数患有KS的男孩都有睾丸功能不全(即睾丸激素缺乏和/或性腺功能减退 症状)从青春期中期开始。出于这个原因，儿科内分泌科医生通常会开出睾丸素。 青春期开始的替代疗法(TRT)。然而，在知识和知识方面仍然存在很大差距 TRT对KS患者脑发育和功能影响的基本问题。事实上，一个宽广的身体 文献表明，青春期男性青春期睾丸素水平的上升会影响一波 神经重塑，神经回路的这些变化与认知的变化密切相关， 行为和情绪。 这里提出的前瞻性、纵向、多时间点研究将是第一次评估 TRT对KS青少年脑发育和功能影响的多水平分析 (认知-行为和社会-情绪功能、多模式成像、青春期状态、激素水平)。 60名患有KS的男孩和60名年龄和智商匹配的神经典型男孩作为对照组，年龄在 9岁和13岁将被招募，并每年跟踪最多四年。三个具体目标将是 解决：(1)考察TRT对KS执行功能和社会情绪症状的影响(2)至 评估TRT对KS患者脑结构和功能的影响，以及(3)阐明KS的脑行为 KS中的关联(探索性)。我们还将检查睾丸功能不全的严重程度作为大脑的调节因素。 二次分析中的行为测量。 我们建议的多学科研究提供了一个首创的机会，以提供更多的 TRT对KS男童认知、行为和情绪影响的研究 青春期周围的时期。这项研究的结果旨在引导改进临床的发展。 KS男童认知行为和社会情绪症状的管理 关于男性青春期认知、行为和情绪的神经变化的常识。

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.