Androgen effect on motor/cognitive outcome in Klinefelter syndrome

描述（由申请人提供）：Klinefelter综合征（KS）是一种发生在1/1000男性中的遗传性疾病，由异常的染色体核型47定义。XXY（额外的X染色体），并且在儿童时期具有明显的特征的身体和认知表型。KS的物理表型包括睾丸功能衰竭（雄激素缺乏）和身材高大。KS神经认知表型包括运动功能减退和基于语言的学习困难。KS行为表现型包括不良的自我形象和害羞。与KS相关的神经发育缺陷可能反映了雄激素缺乏和遗传因素对发育的影响，是KS患者正常生活的主要障碍。这项临床试验的目的是确定是否可以通过在儿童早期使用雄激素替代治疗来减轻这种负担。雄激素替代是青少年和成年KS男性的标准，但尚未用于更年轻，青春期前的KS男孩。第一阶段的研究将确定雄激素奥雄龙，一种fda批准的儿童药物，对青春期前的KS男孩也是安全的。II期研究是一项随机临床试验，我们计划研究儿童雄激素替代对儿童雄激素缺乏可能导致的KS表型的运动和认知方面的影响。这项随机、安慰剂对照的研究在这一人群中测试了一种新的干预措施：对年龄在4-12岁的KS男孩（n=120）进行为期两年的低剂量雄激素（奥雄龙）治疗。我们预测，与安慰剂治疗的KS男孩相比，接受雄激素治疗24个月的KS男孩肌肉力量会有所改善。其次，我们预测，与安慰剂治疗的KS男孩相比，接受雄激素治疗24个月的KS男孩在运动功能方面有改善，包括反应速度、简单重复性运动和复杂的非重复性运动动作。第三，我们预测，接受雄激素（奥雄龙）治疗24个月的KS男孩在语言方面会有所改善，包括口头记忆和语言流畅性。第四，我们预测，与安慰剂治疗的KS男孩相比，接受雄激素治疗24个月的KS男孩在简单和复杂注意力方面都会有所改善。相关研究：KS非常适合介入研究，因为睾丸衰竭在这种疾病中几乎是普遍存在的。在这种雄激素缺乏的人群中，早期雄激素替代是一种合理、适当和安全的研究治疗选择。这种相对常见的疾病的治疗干预措施尚未出现，而这一建议代表了一个独特的机会来替代缺失的激素，并有可能改善运动功能和认知。如果成功，雄激素替代在临床管理KS将开始早期儿童，而不是青春期或成年期。

DESCRIPTION (provided by applicant): Klinefelter syndrome (KS), a genetic disorder that occurs in 1/1000 males, is defined by the abnormal chromosome karyotype 47.XXY (extra X chromosome), and has characteristic physical and cognitive phenotypes evident in childhood. The KS physical phenotype includes testicular failure (androgen deficiency) and tall stature. The KS neurocognitive phenotype includes diminished motor function and language-based learning difficulties. The KS behavioral phenotype involves poor self-image and shyness. The neurodevelopmental deficits associated with KS likely reflect the influence of both androgen deficiency and genetic factors on development and represent a major impediment for living a normal life with KS. It is the goal of this clinical trial to determine whether this burden can be reduced by treatment early in childhood with androgen replacement. Androgen replacement is standard in adolescent and adult KS males but has not been used in younger, prepubertal KS boys. The Phase I study will establish that the androgen oxandrolone, an FDA-approved medication for children, is also safe in prepubertal KS boys. The Phase II study is the randomized clinical trial, in which we plan to study the effects of childhood androgen replacement on motor and cognitive aspects of the KS phenotype that may result from childhood androgen deficiency. This randomized, placebo-controlled study tests a novel intervention in this population: low-dose androgen (oxandrolone) treatment for two years in KS boys (n=120), ages of 4-12 years. We predict that KS boys treated with androgen for 24 months will have improved muscle strength, compared to the placebo-treated KS boys. Second, we predict that KS boys treated with androgen for 24 months will have improved aspects of motor function including response speed, simple repetitive movement, and complex nonrepetitive motor action, compared to the placebo-treated KS boys. Third, we predict that KS boys treated with androgen (oxandrolone) for 24 months will have improved aspects of language, including verbal memory and verbal fluency and fourth, we predict that KS boys treated with androgen for 24 months will have improved aspects of simple and complex attention, compared to the placebo-treated KS boys. RELEVANCE OF THIS RESEARCH: KS is well suited for interventional studies because testicular failure is nearly universal in this disorder. Early androgen replacement is a reasonable, appropriate, and safe research treatment option in this androgen-deficient population. Therapeutic interventions for this relatively common disorder have not been forthcoming, and this proposal represents a unique opportunity to replace a missing hormone and potentially improve motor function and cognition. If successful, androgen replacement in the clinical management of KS would commence early in childhood rather than adolescence or adulthood.