Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, Aarhus C, Denmark.
Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark.
Endocr Rev. 2018 Aug 1;39(4):389-423. doi: 10.1210/er.2017-00212.
Although first identified over 70 years ago, Klinefelter syndrome (KS) continues to pose substantial diagnostic challenges, as many patients are still misdiagnosed, or remain undiagnosed. In fact, as few as 25% of patients with KS are accurately diagnosed and most of these diagnoses are not made until adulthood. Classic characteristics of KS include small testes, infertility, hypergonadothropic hypogonadism, and cognitive impairment. However, the pathophysiology behind KS is not well understood, although genetic effects are also thought to play a role. For example, recent developments in genetics and genomics point to a fundamental change in our understanding of KS, with global epigenetic and RNA expression changes playing a central role for the phenotype. KS is also associated with more general health markers, including higher morbidity and mortality rates and lower socioeconomic status (which likely affect both morbidity and mortality). In addition, hypogonadism is associated with greater risk of metabolic syndrome, type 2 diabetes, cardiovascular disease, breast cancer, and extragonadal germ cell tumors. Medical treatment typically focuses on testosterone replacement therapy (TRT), although the effects of this therapy have not been studied rigorously, and future studies need to evaluate the effects of TRT on metabolic risk and neurocognitive outcomes. This review presents a comprehensive interdisciplinary examination of recent developments in genetic, endocrine, and neurocognitive science, including the study of animal models. It provides a number of recommendations for improving the effectiveness of research and clinical practice, including neonatal KS screening programs, and a multidisciplinary approach to KS treatment from childhood until senescence.
尽管克氏综合征 (KS) 在 70 多年前就已被首次发现，但它仍然存在很大的诊断挑战，因为许多患者仍被误诊，或者仍然未被诊断。事实上，只有 25%的 KS 患者能被准确诊断，而且大多数诊断是在成年后才做出的。KS 的典型特征包括小睾丸、不育、促性腺激素性性腺功能减退和认知障碍。然而，KS 的病理生理学尚未得到很好的理解，尽管遗传效应也被认为起作用。例如，遗传学和基因组学的最新进展表明，我们对 KS 的理解发生了根本性的变化，全球表观遗传和 RNA 表达变化对表型起着核心作用。KS 还与更普遍的健康标志物相关，包括更高的发病率和死亡率以及较低的社会经济地位（这可能影响发病率和死亡率）。此外，性腺功能减退与代谢综合征、2 型糖尿病、心血管疾病、乳腺癌和性腺外生殖细胞肿瘤的风险增加有关。KS 的治疗方法通常侧重于睾酮替代疗法（TRT），尽管尚未对这种治疗方法进行严格研究，未来的研究需要评估 TRT 对代谢风险和神经认知结果的影响。这篇综述全面介绍了遗传学、内分泌学和神经认知科学的最新进展，包括对动物模型的研究。它为提高研究和临床实践的有效性提出了一些建议，包括新生儿 KS 筛查计划，以及从儿童到老年对 KS 进行多学科治疗的方法。
