Disorders of Sex Development: Platform for Basic and Translational Research

性发育障碍（DSD）在表型上是异质的，从轻微的生殖器畸形（尿道下裂、隐睾、阴蒂肥大）到生殖器模糊。总的来说，DSD的估计发病率约为1%。DSD可能对行为健康、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，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，被认为是非常紧张的。最近，关于DSD临床管理的争论，特别是性别分配和生殖器手术，已经加剧;但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存在差距，阻碍了精确的诊断分类，沿着缺乏对健康和生活质量结局的前瞻性纵向研究。 这项建议提供了一个平台，以假设为基础的研究机制的性发展和循证护理的患者和家庭受影响的DSD。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候选基因的鉴定，确定性别发育的新的遗传机制，提高对DSD的病理生理学和分子诊断的理解。Aim 2为多个研究中心和研究者提供了可靠的表型描述的标准化工具，包括放射学、生物化学、组织学评估和生殖器表型以及手术后外观和功能的描述，便于解释遗传、性别、目标3通过提供全面的社会心理和健康服务，确定短期和中期结果，相关的生活质量评估组合，使用心理测量学上的稳健措施，适用于常规临床护理，这是导致循证心理社会治疗方案的必要步骤。目标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，确保新证据快速转化为正在进行的临床实践，并促进在网络站点之间转移医疗保健服务的最佳实践。该注册表提供了一个分析平台，通过该平台，研究人员和研究中心可以收集、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研究的研究中心转变为自我维持的DSD“卓越中心”，用于临床护理，同时沿着登记处作为假设驱动研究的关键资源的附加值。

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.