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

非凡婴儿研究：性染色体三体婴幼儿健康和神经发育的自然史

• 批准号: 10228690
• 负责人: Nicole Renee Tartaglia
• 金额: $ 51.86万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2023-04-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228690
• 关键词: 4 year old; 5 year old; Academic achievement; Adolescence; Adult; Age; Age-Years; American; Androgen Therapy; Androgens; Behavior; Birth; Body Composition; Body fat; Caring; Child; Childhood; Chromosome abnormality; Clinic; Cognitive; Common Data Element; Congenital Abnormality; Counseling; Data; Development; Developmental Delay Disorders; Diagnosis; Discipline of obstetrics; Disease; Early Intervention; Educational Intervention; Eligibility Determination; Epidemic; Evidence based treatment; Failure; Family; Future; Genetic Counseling; Genomics; Genotype; Gold; Gonadal Steroid Hormones; Guidelines; Gynecology; Health; Heterogeneity; High-Risk Pregnancy; Hormonal; Infant; Insulin Resistance; Intervention; Intervention Studies; Intervention Trial; Investigation; Klinefelter' s Syndrome; Knowledge; Language; Language Development; Language Disorders; Lead; Learning Disabilities; Learning Disorders; Leptin; Life; Linear Models; Logistic Regressions; Longevity; Longitudinal Studies; Longitudinal prospective study; Measures; Medical; Medical Genetics; Mental Health; Metabolic syndrome; Methods; Modeling; Morbidity - disease rate; Motor; Natural History; Neonatal Screening; Neurodevelopmental Problem; Newborn Infant; Outcome; Ovarian; Pattern; Phenotype; Physical Examination; Pregnancy; Prenatal Diagnosis; Primary Health Care; Prospective Studies; Protocols documentation; Puberty; Quality of life; Recommendation; Recording of previous events; Reporting; Research; Risk; Risk Factors; Sampling; School-Age Population; Screening procedure; Seizures; Sex Chromosomes; Shapes; Site; Social Interaction; Speech; Statistical Models; Supporting Cell; Temperament; Test Result; Testing; Time; Translational Research; Trisomy; Trisomy 2; Trisomy X syndrome; Visit; Work; XYY Karyotype; autism spectrum disorder; biobank; cardiometabolic risk; cardiometabolism; cell free DNA; clinical care; cohort; college; comorbidity; critical period; demographics; disorder risk; early childhood; emotional functioning; evidence base; gonad function; high risk; high risk population; improved; infancy; learned behavior; literacy; metabolic rate; mortality; neurodevelopment; ovarian failure; patient oriented; physical conditioning; prenatal; prenatal testing; prospective; psychological outcomes; screening; skills; social; social attention; social skills; standardize measure; treatment guidelines

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.

背景：性染色体三体 (SCT) 包括克氏 (XXY)、X 三体 (XXX) 和 XYY 综合征，每 500 名新生儿中就有 1 人发生，并与广泛的表型谱相关，包括发育迟缓 (DD)、语言风险增加/学习障碍和自闭症谱系障碍 (ASD) 也与睾丸衰竭有关，XXX 会增加卵巢衰竭的风险，以及导致胰岛素抵抗和其他医疗问题的风险。所有 3 种 SCT 的发病率和死亡率均有所增加，从历史上看，只有不到 10% 的 SCT 诊断发生在儿童期，但随着新的非侵入性产前无细胞 DNA (cfDNA) 筛查，新生儿 SCT 的发生率显着增加。仅限于 20 世纪 70 年代的研究，我们对后期结果的广泛异质性的早期预测因素知之甚少。 XXY 可以改善发育和健康结果，支持新生儿筛查的需要，以便在这一关键时期进行干预。SCT 中 DD 的极高风险也表明新生儿筛查可以改善干预措施的及时启动。 然而，尚不清楚是否所有 SCT 婴儿确实都需要强化发育评估和治疗，或者 如果初级保健筛查足以识别有需要的人，通过 cfDNA 方法进行的产前 SCT 诊断的激增为对一组婴儿进行纵向研究以探索自然史和改善护理提供了机会。 目的：本研究旨在：(1) 通过与新生儿筛查转化研究网络 (NBSTRN) 合作开展的一项全国性前瞻性异常婴儿研究，描述和比较患有 3 种 SCT 病症的婴儿的神经发育、健康和早期性腺功能的自然史，(2) 确定神经发育和心脏代谢结果不良的早期预测因素，(3) 评估常见初级保健发育筛查措施的敏感性，以检测 DD 和 ASD这个高风险人群为早期神经发育护理方案提供建议。 方法：产前诊断为 XXY (n=100)、XYY (n=50) 或 XXX (n=50) 的婴儿将在 2 个 eXtraordinalY 儿童诊所每 6-12 个月进行前瞻性随访，为期 2-4 年。将使用 NBSTRN 通用数据元素收集人口统计、健康史、发育、干预措施和社会/家族史。评估将包括：(1) 认知、语言、社交、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成分，以及 (3) 生活质量结果将针对每种 SCT 状况的发育和激素概况以及早期风险之间的关联进行建模。此外，将使用直接发育测试结果作为金标准来计算常见初级保健 DD 和 ASD 筛查的敏感性。对产前诊断的 SCT 婴儿的自然病史进行研究将有助于调查重要问题，为新生儿筛查考虑因素提供信息，例如早期荷尔蒙分布和发育结果之间的相互作用，结果将立即与咨询和建立基于证据的护理指南相关。 cfDNA 筛查的 SCT 诊断率迅速增加，结果将作为对 SCT 整个生命周期的健康和心理结果进行持续纵向研究的基础。