Disorders of Sex Development: Platform for Basic and Translational Research

性发育障碍（DSD）在表型上是异质性的，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的发生率估计约为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，被认为是非常紧张的。最近，关于DSD的临床管理，特别是性别分配和生殖器手术的争论愈演愈烈；然而，关于患者预后的科学数据仍然非常不完整。对DSD进行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，以及缺乏对健康和生活质量结果的前瞻性纵向研究。

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.