Disorders of Sex Development: Platform for Basic and Translational Research

描述(由申请人提供)：性发育障碍(DSD)是一种表型不同的疾病，从轻微的生殖器畸形(尿道下裂、隐睾症、阴蒂肥大)到生殖器不明确。总体而言，DSD的发病率估计约为1%。DSD会对行为健康、生育能力、癌症风险和生活质量造成严重后果。对于家庭来说，一个患有DSD的孩子的出生，以及随之而来的对未来心理和性发展的不确定性，被认为是非常有压力的。最近，关于DSD的临床管理，特别是性别分配和生殖器手术的辩论愈演愈烈；然而，关于患者结局的科学数据仍然非常不完整。DSD最佳临床管理的主要障碍包括对病理生理学的理解差距，阻碍准确的诊断分类，以及缺乏对健康和生活质量结果的前瞻性纵向研究。这一建议为基于假设的研究提供了一个平台，为受DSD影响的患者和家庭的性发育和循证护理机制提供了一个平台。目的1通过特异性DNA捕获和测序、拷贝数变异分析和新的DSD候选基因鉴定的逐步方法，确认性发育的新的遗传机制，提高对DSD的病理生理和分子诊断的理解。目标2为多个研究地点和研究人员提供可靠的表型描述的标准化工具，包括放射学、生化、组织学评估以及生殖器表型和手术后外观和功能的描述，促进对遗传、性别和生活质量结果的解释，目标3通过使用适合于常规临床护理的心理测量学稳健措施提供全面的心理社会和健康相关生活质量评估单元，确定短期和中期结果，这是导致基于证据的心理社会治疗方案的必要步骤。AIM 4建立了一个可持续的研究基础设施，并通过整合标准化的DSD诊断和治疗方案并促进医疗保健提供的最佳实践跨网络站点的转移，确保将新证据快速转化为持续的临床实践。这个注册中心提供了一个分析平台，通过它可以在研究人员和站点之间收集、分析和共享数据，而协作网络将为多学科基础、临床和转化性研究提供基础。这种遗传、表型和心理社会方法的独特组合将把参与站点转变为自给自足的DSD临床护理“卓越中心”，同时注册的附加值作为假说驱动的研究的关键资源。 与公共健康相关：我们生命中最具决定性的时刻之一是，在子宫中，我们走上了男性或女性的道路。典型的男性或女性发育中断，无论是轻微的还是严重的，都会导致性发育障碍(DSD)，这种疾病在大约1%的人类人口中经常发生。DSD给父母带来极大的压力，随着他们年龄的增长，受影响的人也会受到影响，并经常伴随着额外的医疗和心理问题；然而，人们对DSD的原因以及医疗团队在短期和长期应该做些什么知之甚少。我们建议设计一种方法来了解DSD的遗传原因和心理后果，并利用这些数据为医疗团队提供评估和改善对这些患者及其家人的护理的程序。

DESCRIPTION (provided by applicant): Disorders of sex development (DSD) are phenotypically heterogeneous, ranging from minor genital malformations (hypospadias, cryptorchidism, hypertrophy of the clitoris) to genital ambiguity. In the aggregate, DSD have an estimated incidence of about 1%. DSD can result in severe consequences for behavioral health, fertility, cancer risk and quality of life. For families, the birth of a child with a DSD, and the accompanying uncertainty about future psychological and sexual development, is believed to be extraordinarily stressful. Recently, the debate over clinical management of DSD, in particular gender assignment and genital surgery, has intensified; yet the scientific data on patient outcomes have remained very incomplete. Major obstacles to optimal clinical management of DSD include gaps in understanding of pathophysiology, impeding precise diagnostic categorization, along with the absence of prospective longitudinal studies of health and quality of life outcomes. This proposal delivers a platform for hypothesis-based research on the mechanisms of sex development and evidence-based care for patients and families affected by DSD. Aim 1 identifies novel genetic mechanisms of sex development and improves understanding of the pathophysiology and molecular diagnosis of DSD by a step-wise approach of specific DNA capture and sequencing, analysis of copy number variants, and identification of novel candidate genes for DSD. Aim 2 delivers standardized tools for reliable phenotypic descriptions across multiple study sites and investigators, including radiological, biochemical, histological evaluations and descriptions of genital phenotype and post- surgical appearance and function, facilitating interpretation of genetic, gender, and quality of life outcomes Aim 3 identifies short and medium-term outcomes by delivering a comprehensive psychosocial and health-related quality of life assessment battery using psychometrically robust measures suitable for use in routine clinical care, a necessary step leading to evidence-based psychosocial treatment protocols. Aim 4 builds a sustainable research infrastructure and ensures rapid translation of new evidence into ongoing clinical practice by integrating standardized DSD diagnostic and treatment protocols and fostering the transfer of best practices in healthcare delivery across network sites. This registry provides the analytic platform by which data are collected, analyzed, and shared among researchers and sites, while a collaborative network will supply the foundation for multidisciplinary basic, clinical, and translational research. This unique combination of genetic, phenotypic and psychosocial approaches will transform participating sites into self-sustaining DSD "centers of excellence" for clinical care along with the added value of a registry serving as a critical resource for hypothesis-driven research. PUBLIC HEALTH RELEVANCE: One of the most defining moments of our lives is when, in the womb, we embark on a male or female path. Disruption of typical male or female development, whether mild or severe, results in Disorders of Sex Development (DSD), which occur quite frequently, in about 1% of the human population. DSD are extremely stressful for parents and, as they grow older, the affected person and are often accompanied by additional medical and psychological problems; yet little is known about the causes of DSD and what healthcare teams should do in the short and long term. We propose to design a way to learn about the genetic causes and the psychological consequences of DSD, and to use these data to provide healthcare teams with procedures to evaluate and improve care for these patients and their families.