The eXtraordinarY Babies Study: Natural History of Health and Neurodevelopment in Infants and Young Children with Sex Chromosome Trisomy

项目摘要 背景：性染色体三体（SCT）包括Klinefelter（XXY）、X三体（XXX）和XYY综合征， 每500名新生儿中就有1例，并与广泛的表型谱相关，包括发育迟缓的风险增加 (DD)语言/学习障碍和自闭症谱系障碍（ASD）。XXY还与睾丸衰竭有关，XXX 增加卵巢功能衰竭的风险，胰岛素抵抗和其他医疗问题的障碍，导致增加 发病率和死亡率发生在所有3种SCT中。从历史上看，不到10%的SCT诊断发生在儿童时期，然而， 新生儿SCT与新的非侵入性产前无细胞DNA（cfDNA）筛查显着增加。SCT自然 历史研究仅限于20世纪70年代的研究，我们对广泛的早期预测者知之甚少。 后期结果的异质性。越来越多的研究表明，在婴儿期雄激素治疗XXY可能会改善 发展和健康结果，支持新生儿筛查的需要，以便在此期间提供干预措施。 关键时期。SCT中DD的极高风险也表明新生儿筛查可改善及时启动 干预措施。然而，目前尚不清楚是否所有SCT婴儿确实需要强化发育评估和治疗， 如果初级保健筛查足以识别那些需要的人。来自cfDNA方法的产前SCT诊断激增 提供了一个机会，纵向研究一组婴儿，探索自然史，并改善护理。 目的：本研究旨在：（1）描述和比较神经发育、健康和早期性腺发育的自然史 通过一项全国性的前瞻性超常规婴儿研究， 新生儿筛查转化研究网络（NBSTRN），（2）确定神经发育不良的早期预测因子， 心脏代谢结果，（3）评估常见的初级保健发育筛查措施的敏感性， 在这一高危人群中检测DD和ASD，为早期神经发育护理方案提供建议。 方法：将前瞻性随访产前诊断为XXY（n=100）、XYY（n=50）或XXX（n=50）的婴儿， 6 - 12个月，2 - 4年，在2个eExtraordinarY Kids Clinic中心。人口统计学、健康史、发育、干预措施和 将使用NBSTRN通用数据元素收集社会/家族史。评估将包括：（1） 认知、语言、社会、运动和适应功能，（2）体格检查，性腺功能实验室，心脏代谢测量， 和身体组成，以及（3）生活质量结果。每种SCT条件的发育和激素特征将被 模型，并将测试早期风险因素与3 - 4岁结局之间的相关性。此夕h 将使用直接发育试验计算普通初级保健DD和ASD筛查仪对每种疾病的敏感性 结果为黄金标准。影响：对产前诊断患有SCT的婴儿的自然史进行前瞻性研究， 调查重要问题，以告知新生儿筛查考虑因素，例如早期 激素分布和发育结果。结果将立即相关的咨询和建立 循证护理指南，用于cfDNA筛查中SCT诊断率迅速增加。结果将作为基础 对SCT在整个生命周期中的健康和心理结果进行持续的纵向研究。

PROJECT SUMMARY Background: Sex Chromosome Trisomies (SCT) including Klinefelter (XXY), Trisomy X (XXX), and XYY syndromes occur in 1 out of every 500 births and are associated with a broad phenotypic spectrum including increased risk for developmental delays (DD), language/learning disorders, and autism spectrum disorder (ASD). XXY is also associated with testicular failure, XXX increases risk for ovarian failure, and disorders of insulin resistance and other medical problems resulting in increased morbidity and mortality occur in all 3 SCTs. Historically, less than 10% of SCT diagnoses occur in childhood, however the rate of newborns with SCT has markedly increased with new noninvasive prenatal cell‐free DNA (cfDNA) screening. SCT natural history research is limited to studies from the 1970's, and we have little knowledge of early predictors of the wide heterogeneity in later outcomes. Increasing research suggests that androgen therapy during infancy in XXY may improve developmental and health outcomes, supporting the need for newborn screening so intervention can be delivered during this critical period. The very high risk for DD in SCT also suggests that newborn screening may improve timely initiation of interventions. However, it is not clear whether all SCT infants indeed require intensive developmental assessments and therapies, or if primary care screenings are sufficient to identify those in need. The surge in prenatal SCT diagnoses from cfDNA methods provides an opportunity for longitudinal study of a cohort of infants to explore natural history, and to improve care. Aims: This study aims to: (1) describe and compare the natural history of neurodevelopment, health and early gonadal function in infants with the 3 SCT conditions through a national prospective eXtraordinarY Babies Study in partnership with the Newborn Screening Translational Research Network (NBSTRN), (2) identify early predictors of poor neurodevelopmental and cardiometabolic outcomes, and (3) evaluate the sensitivities of common primary care developmental screening measures to detect DD and ASD in this high‐risk population to inform recommendations for an early neurodevelopmental care protocol. Approach: Infants with a prenatal diagnosis of XXY (n=100), XYY (n=50), or XXX (n=50) will be followed prospectively every 6‐12 months for 2‐4 years at 2 eXtraordinarY Kids Clinic sites. Demographics, health history, development, interventions, and social/family history will be collected using NBSTRN common data elements. Assessments will include: (1) measures of cognitive, language, social, motor, and adaptive function, (2) physical exam, gonadal function labs, cardiometabolic measures, and body composition, and (3) quality of life outcomes. Developmental and hormonal profiles for each SCT condition will be modeled, and the association between early risk factors and outcomes at 3‐4 years of age will be tested. Further, the sensitivities of common primary care DD and ASD screeners will be calculated for each condition using direct developmental test results as gold‐standard. Impact: Prospective study of the natural history of prenatally diagnosed infants with SCT will allow investigation of important questions to inform newborn screening considerations, such as the interplay between early hormonal profiles and developmental outcomes. Results will be immediately relevant for counseling and establishing evidence‐based care guidelines for the rapidly increasing rate of SCT diagnoses from cfDNA screening. Results will serve as the basis for ongoing longitudinal studies of health and psychological outcomes of SCTs through the lifespan.