Androgen effect on motor/cognitive outcome in Klinefelter syndrome

描述（由申请人提供）：Klinefelter综合征（KS）是一种遗传性疾病，发生于1/1000的男性，由异常染色体核型47.XXY（额外X染色体）定义，具有儿童期明显的特征性身体和认知表型。KS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行为表型包括自我形象差和害羞。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进行雄激素替代治疗来减轻这种负担。雄激素替代治疗在青少年和成年KS男性中是标准的，但尚未用于年轻的青春期前KS男孩。第一阶段的研究将确定，雄激素氧雄龙，FDA批准的儿童药物，也是安全的青春期前KS男孩。II期研究是一项随机临床试验，我们计划研究儿童期雄激素替代治疗对可能由儿童期雄激素缺乏引起的KS表型的运动和认知方面的影响。这项随机、安慰剂对照研究在这一人群中测试了一种新的干预措施：在4-12岁的KS男孩（n=120）中进行为期两年的低剂量雄激素（氧雄龙）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男孩将改善肌肉力量。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男孩将改善运动功能，包括反应速度，简单重复运动和复杂的非重复运动动作。第三，我们预测，KS男孩与雄激素（氧雄龙）治疗24个月将有改善方面的语言，包括言语记忆和言语流畅性和第四，我们预测，KS男孩与雄激素治疗24个月将有改善方面的简单和复杂的注意力，相比安慰剂治疗的KS男孩。本研究的相关性：KS非常适合介入研究，因为睾丸功能衰竭在这种疾病中几乎是普遍的。早期雄激素替代治疗是一个合理的，适当的，安全的研究治疗选择，在这个雄激素缺乏的人群。这种相对常见的疾病的治疗干预措施尚未出现，这一建议代表了一个独特的机会，以取代缺失的激素和潜在的改善运动功能和认知。如果成功，雄激素替代治疗KS的临床管理将在儿童早期开始，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.