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Klinefelter(XXY)、X三体(XXX)和XYY综合征，每500个新生儿中就有一个发生，并与广泛的表型谱相关，包括发育迟缓(DD)、语言/学习障碍和自闭症谱系障碍(ASD)的风险增加。XXY还与睾丸功能衰竭有关，XXX增加卵巢功能衰竭的风险，胰岛素抵抗紊乱和其他医学问题导致发病率和死亡率在所有三种SCT中都会发生。历史上，只有不到10%的SCT诊断发生在儿童时期，然而，随着新的无创性产前无细胞DNA(CfDNA)筛查，患有SCT的新生儿的比例显著增加。SCT自然史研究仅限于20世纪70年代S以来的研究，我们对后来结果的广泛异质性的早期预测因素知之甚少。越来越多的研究表明，XXY婴儿期的雄激素治疗可能会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中发生DD的风险非常高，这也表明新生儿筛查可能有助于及时启动干预措施。 然而，尚不清楚是否所有的SCT婴儿确实需要密集的发育评估和治疗，或者 初级保健筛查是否足以识别有需要的人。通过cfDNA方法进行产前SCT诊断的激增为对一组婴儿进行纵向研究探索自然病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)合作的全国前瞻性特殊婴儿研究，描述和比较患有3种SCT疾病的婴儿的神经发育、健康和早期性腺功能的自然历史，(2)识别神经发育和心脏代谢不良结局的早期预测因素，以及(3)评估在这一高危人群中检测DD和ASD的常见初级保健发育筛查措施的敏感性，以便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)的婴儿在两个特别儿童诊所每隔6-12个月进行一次前瞻性追踪，为期2-4年。将使用NBSTRN公共数据元素收集人口统计数据、健康史、发展史、干预措施和社会/家庭史。评估将包括：(1)认知、语言、社交、运动和适应功能的测量；(2)体检、性腺功能实验室、心脏代谢测量和身体成分；(3)生活质量结果。将模拟每种SCT条件下的发育和荷尔蒙情况，并测试早期风险因素与3-4岁儿童预后之间的关系。此外，普通初级保健DD和ASD筛查的敏感性将以直接发育测试结果为金标准计算每种情况的敏感度。影响：对产前诊断为SCT的婴儿的自然病史的前瞻性研究将允许调查重要的问题，以便为新生儿筛查考虑提供信息，例如早期荷尔蒙特征和发育结果之间的相互作用。结果将与咨询和建立循证护理指南直接相关，以应对cfDNA筛查迅速增加的SCT诊断率。研究结果将作为SCTS患者整个生命周期健康和心理结果的持续纵向研究的基础。