Delayed Puberty: Causes and Consequences, Genotypes and Phenotypes

项目概要/摘要 该项目旨在加强我们对临床特征，长期后果， 青春期延迟的遗传基础，这是一种影响2-3%青少年的常见疾病。而 据报道，青春期延迟对最终身高、骨密度和自我发育有负面影响。 尽管成年人的自尊心很强，但仍不清楚哪些青春期延迟的患者最有可能患上这些疾病， 结果。此外，我们对生理和遗传机制的了解有限， 导致青春期延迟 这个项目治疗青春期延迟不是作为一个单一的，整体的实体，但作为一个临床表型，可以 至少有两种机制。一个机制是全球发展计划的放缓， 不仅调节青春期的时间，还调节儿童生长和骨骼成熟的速度;这 全球性生长迟缓通常被称为体质性生长和青春期延迟（CDGP）。另一种机制是 在没有其他生长或骨骼成熟延迟的情况下，青春期时间延迟，产生孤立的 青春期延迟。这些机制并不相互排斥，两者都可能有助于 个体的青春期延迟。 本项目的第一个目的是通过回顾临床资料，探讨青春期延迟的临床异质性。 青春期延迟患者的记录，并使用单变量和 多变量分析目标1还将使用潜在类分析，一个公正的，数据驱动的方法，以确定 青春期延迟的不同亚组。 该项目的第二个目的是评估有青春期延迟史的成年人，以确定这些人是否有青春期延迟史。 成年人在身高、骨密度、自尊或精子数量（男性）方面有障碍， 正常青春期时间的健康对照成年人。Aim进一步评估这些结果是否 在目标1中确定的青春期延迟的不同亚组和/或预测变量之间存在差异， 如性别、体重指数和既往性类固醇治疗。 本项目的第三个目的是通过检查 罕见变异（通过全外显子组测序鉴定）和常见变异的贡献 （通过单核苷酸多态性的基因分型鉴定）。这一目标也将把这些遗传原因联系起来 目标1中确定的青春期延迟亚组和目标2中检查的成人结局。 通过确定青春期延迟的病理生理机制和遗传原因，以及 与这些因素相关的临床结果，这些研究将提高我们对常见的 儿科条件，并可能导致新的见解的奥秘，如何儿童成长的速度， 青春期的时间是确定的。

Project Summary/Abstract This project seeks to enhance our understanding of the clinical features, long-term consequences, and genetic underpinnings of delayed puberty, a common condition that affects 2-3% of adolescents. While delayed puberty has been reported to have negative effects on final height, bone mineral density, and self- esteem in adulthood, it remains unclear which patients with delayed puberty are at greatest risk for these outcomes. Furthermore, we have limited understanding of the physiological and genetic mechanisms that underlie delayed puberty. This project treats delayed puberty not as a single, monolithic entity, but as a clinical phenotype that can be produced by at least two mechanisms. One mechanism is a global slowing of the developmental program that regulates not just the timing of puberty but also the pace of childhood growth and skeletal maturation; this global slowing is often called constitutional delay of growth and puberty (CDGP). The other mechanism is a delay in pubertal timing in the absence of other delays in growth or skeletal maturation, producing an isolated delay in pubertal timing. These mechanisms are not mutually exclusive, and both could potentially contribute to delayed puberty in an individual. The first Aim of this project explores the clinical heterogeneity in delayed puberty by reviewing clinical records of delayed puberty patients and identifying correlations between variables using univariate and multivariate analyses. Aim 1 will also use latent class analysis, an unbiased, data-driven method, to identify distinct subgroups within delayed puberty. The second Aim of this project assesses adults with a history of delayed puberty to determine if these adults have impairments in height, bone mineral density, self-esteem, or sperm counts (in men) compared to healthy control adults who had normal pubertal timing. The Aim further assesses whether these outcomes differ for the different subgroups of delayed puberty identified in Aim 1 and/or across predictor variables such as sex, body mass index, and prior treatment with sex steroids. The third Aim of this project seeks to identify the genetic causes of delayed puberty by examining the contributions of both rare variants (identified through whole-exome sequencing) and common variants (identified through genotyping of single-nucleotide polymorphisms). This Aim will also link these genetic causes to the subgroups of delayed puberty identified in Aim 1 and the adult outcomes examined in Aim 2. By identifying the pathophysiologic mechanisms and genetic causes underlying delayed puberty, as well as the clinical outcomes associated with these factors, these studies will improve our understanding of a common pediatric condition and may lead to new insights into the mysteries of how the pace of childhood growth and the timing of puberty are determined.