Supplementary Material for: Approaches to Identify Factors Associated with Pubertal Timing in Self-Limited Delayed Puberty

Introduction: Children with self-limited delayed puberty (constitutional delay) enter puberty after variable waiting times, and the factors associated with their eventual pubertal timing are not well understood. Methods: We conducted a retrospective study of 99 girls and 228 boys with self-limited delayed puberty (DP) at an academic medical center between 2000 and 2015. To define features and potential subtypes of self-limited DP, we performed group-based trajectory modeling on childhood growth and latent-variable factor analysis on clinical characteristics. We then conducted time-to-event analyses to identify associations with pubertal timing. Results: We identified two distinct growth trajectories in individuals with self-limited DP: one with stable and the other with declining height percentiles. Latent-variable factor analysis identified five factors underlying clinical variation that appear to correspond to genetic height potential, body mass index, childhood growth, parental pubertal delay, and medical issues (attention-deficit/hyperactivity disorder and inhaled glucocorticoid use). We observed correlations between pubertal timing and bone age (p=0.01), childhood height (p=0.004), and midparental target height (p<0.001), but not with parental pubertal delay or with testosterone treatment in boys. Conclusions: By illustrating the heterogeneity within self-limited DP and identifying factors underlying this heterogeneity, our study suggests that there may be multiple causes of self-limited DP. However, our ability to determine when puberty will eventually occur remains limited. Dissecting self-limited DP into its component subtypes may inform future studies of the mechanisms contributing to pubertal delay as well as studies of the short- and long-term outcomes of self-limited DP.

引言：患有自限性青春发育延迟（self-limited delayed puberty，又称体质性延迟（constitutional delay））的儿童，其青春发育启动的等待时长存在显著个体差异，目前学界对与其最终青春发育启动时间相关的影响因素尚缺乏充分认知。方法：本研究于2000年至2015年间，在某教学医学中心纳入99名女童、228名男童，这些受试者均患有自限性青春发育延迟（delayed puberty，DP），研究类型为回顾性研究。为明确自限性青春发育延迟的临床特征与潜在亚型，我们针对受试者的儿童期生长数据开展基于分组的轨迹建模，并针对临床特征实施潜变量因子分析；随后通过事件发生时间分析（time-to-event analyses），探究各项指标与青春发育启动时间的关联。结果：本研究在自限性青春发育延迟患者中识别出两类截然不同的生长轨迹：一类为身高百分位数维持稳定，另一类则呈下降趋势。潜变量因子分析显示，该人群的临床异质性由5种核心因素驱动，分别对应遗传身高潜力、体重指数（body mass index，BMI）、儿童期生长状况、父母青春发育延迟史，以及合并疾病（注意缺陷多动障碍（attention-deficit/hyperactivity disorder，ADHD）与吸入性糖皮质激素使用史）。研究发现，青春发育启动时间与骨龄（p=0.01）、儿童期身高（p=0.004）以及亲代靶身高（midparental target height）（p<0.001）存在显著相关性，但与父母青春发育延迟史及男性受试者的睾酮治疗无明显关联。结论：本研究通过阐明自限性青春发育延迟的异质性并明确其驱动因素，提示自限性青春发育延迟可能存在多种致病机制；但目前我们仍难以准确预测个体的青春发育启动时间。将自限性青春发育延迟拆解为不同亚型，可为探究青春发育延迟的发病机制，以及开展自限性青春发育延迟的短期与长期转归研究提供参考方向。