Delayed Puberty: Causes and Consequences, Genotypes and Phenotypes

项目摘要/摘要 该项目旨在加强我们对临床特征、长期后果和 青春期延迟的遗传基础，这是一种常见的疾病，影响2-3%的青少年。而当 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。 成年期的尊重，目前还不清楚哪些青春期延迟的患者患这些疾病的风险最大 结果。此外，我们对生理和遗传机制的了解也有限。 导致青春期延迟。 这个项目不是将青春期延迟作为一个单一的整体，而是作为一种临床表型，可以 至少由两种机制产生的。一种机制是全球发展计划的放缓， 不仅调节青春期的时间，而且调节儿童成长和骨骼成熟的速度；这 全球经济放缓通常被称为宪法上的生长和青春期延迟(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，青春期的延迟，产生孤立的 青春期计时延迟。这些机制并不是相互排斥的，两者都可能有助于 个体的青春期延迟。 这个项目的第一个目的是通过回顾临床研究来探索青春期延迟的临床异质性。 青春期延迟患者的病历记录及变量间的相关性分析 多变量分析。目标1还将使用潜在类别分析，这是一种无偏见的数据驱动方法，以识别 青春期延迟的不同亚群。 该项目的第二个目标是评估有青春期延迟病史的成年人，以确定这些 与男性相比，成年人的身高、骨密度、自尊或精子数量都有损害。 青春期发育时间正常的健康对照成年人。目的是进一步评估这些结果是否 对于目标1中确定的不同的青春期延迟亚组和/或不同的预测变量 作为性别，体重指数，以及之前的性激素治疗。 这个项目的第三个目标是通过检查青春期发育迟缓的基因 稀有变异(通过全外显子测序鉴定)和常见变异的贡献 (通过单核苷酸多态基因分型鉴定)。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 临床转归与这些因素相关，这些研究将提高我们对一个共同的 儿科疾病，并可能导致对儿童生长和发育速度如何的谜团有新的见解 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.