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

背景资料：性染色体三体综合征（SCT），包括克兰费尔特综合征（XXY）、X三体综合征（XXX）和XYY综合征，每500例新生儿中有1例发生，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还与睾丸衰竭相关，XXX增加卵巢衰竭的风险，胰岛素抵抗疾病和其他医学问题导致所有3种SCT的发病率和死亡率增加。从历史上看，不到10%的SCT诊断发生在儿童时期，然而，随着新的无创产前无细胞DNA（cfDNA）筛查，新生儿SCT的发病率显着增加。SCT自然史研究仅限于20世纪70年代的研究，我们对后期结果中广泛异质性的早期预测因子知之甚少。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，以便在这个关键时期进行干预。SCT中DD的极高风险也表明，新生儿筛查可能有助于及时启动干预措施。 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诊断的激增为婴儿队列的纵向研究提供了机会，以探索自然史并改善护理。 目的：本研究旨在：（1）通过与新生儿筛查转化研究网络（NBSTRN）合作开展的国家前瞻性超常规婴儿研究，描述并比较3种SCT条件下婴儿的神经发育、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不良结局的早期预测因子，和（3）评价常见初级保健发育筛查措施在该高危人群中检测DD和ASD的敏感性，以提供早期神经发育护理方案的建议。 方法：产前诊断为XXY（n=100）、XYY（n=50）或XXX（n=50）的婴儿将在2个ExtraordinarY Kids Clinic中心每6 - 12个月进行一次前瞻性随访，持续2 - 4年。将使用NBSTRN通用数据元素收集人口统计学、健康史、发育、干预和社会/家族史。评估将包括：（1）认知、语言、社会、运动和适应功能的测量，（2）体格检查、性腺功能实验室、心脏代谢测量和身体成分，以及（3）生活质量结果。将对每种SCT疾病的发育和激素特征进行建模，并将检测早期风险因素与3 - 4岁时结局之间的相关性。此外，将使用直接发育测试结果作为金标准，计算普通初级保健DD和ASD筛查仪对每种疾病的敏感性。影响：对产前诊断为SCT的婴儿的自然史进行前瞻性研究，将允许调查重要问题，以告知新生儿筛查考虑因素，例如早期激素谱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cfDNA筛查的SCT诊断率快速增加的循证护理指南相关。结果将作为正在进行的SCT在整个生命周期中的健康和心理结果的纵向研究的基础。

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.