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：性别染色体Trisomies（SCT），包括KlineFelter（XXY），Trisome X（XXX）和XYY综合症，每500个出生中有1个出现，并且与广泛的表型谱系相关，包括增加的发展风险（包括发育迟缓）（DD），语言/学习障碍和自动化型谱系障碍（ASD）。 XXY还与实证失败有关，XXX增加了卵巢衰竭的风险，胰岛素抵抗和其他医疗问题的疾病导致发病率和死亡率增加，这3个SCT中均出现。从历史上看，只有不到10％的SCT诊断发生在童年时期，但是随着新的非侵入性产前无细胞的DNA（CFDNA）筛查，具有SCT的新生儿率显着增加。 SCT自然史研究仅限于1970年代的研究，我们对以后结果的广泛异质性的早期预测因素知之甚少。增加的研究表明，XXY婴儿期在XXY中的雄激素疗法可以改善发展和健康结果，从而支持对新生儿筛查的需求，因此可以在这个关键时期进行干预。 SCT中DD的极高风险还表明，新生儿筛查可以及时提高干预措施的启动。 但是，尚不清楚所有SCT婴儿是否确实需要进行密集的发育评估和疗法，或者 如果初级保健筛查足以确定有需要的人。 CFDNA方法的产前SCT诊断激增为纵向研究的婴儿提供了机会，以探索自然史并改善护理。 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 sensitivity of common primary care developmental screening在此高风险人群中检测DD和ASD的措施为早期神经发育护理方案提供了建议。 方法：患有XXY产前诊断的婴儿（n = 100），XYY（n = 50）或XXX（n = 50）可能会在2个非凡的儿童诊所地点每6-12个月一次每6-12个月进行2 - 4年。人口统计学，健康历史，发展，干预和社会/家族史将使用NBSTRN通用数据元素收集。评估将包括：（1）认知，语言，社交，运动和适应性功能的测量，（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）生活质量的质量。每个SCT条件的发育和马剖面将进行建模，并将测试早期危险因素与结果之间的关联。此外，将使用直接发展测试结果作为金标准来计算每种条件的普通初级保健DD和ASD筛选器的敏感性。影响：对患有SCT产前诊断的婴儿的自然历史的前瞻性研究将允许对重要问题进行调查，以告知新生儿筛查考虑因素，例如早期的牛角概况与发育结果之间的相互作用。结果将立即与咨询和建立循证护理指南有关CFDNA筛查迅速增加的SCT诊断率。结果将作为对SCT的健康和心理结局进行持续纵向研究的基础。