Disorders of Sex Development: Platform for Basic and Translational Research

性发育障碍：基础和转化研究平台

• 批准号: 8883222
• 负责人: DAVID Eric. SANDBERG
• 金额: $ 83.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883222
• 关键词: Accounting; Advocate; Affect; Algorithms; Anatomy; Appearance; Basic Science; Biochemical; Biological; Biology; Birth; Candidate Disease Gene; Child; Clinical; Clinical Management; Clinical Research; Clitoris; Consensus; Copy Number Polymorphism; Cryptorchidism; DNA; Data; Decision Making; Development; Diagnosis; Diagnostic; Effectiveness; Emotional; Ensure; Environment; Equilibrium; Europe; European Union; Evaluation; Family; Female; Fertility; Financial Support; Fostering; Foundations; Functional disorder; Future; Gender; Genetic; Genital system; Genotype; Goals; Guidelines; Health; Health Personnel; Health Professional; Healthcare; Healthcare Systems; Human; Hypertrophy; Hypospadias; Incidence; Information Technology; Interdisciplinary Study; Investigation; Knowledge; Leadership; Learning; Left; Link; Longevity; Longitudinal Studies; Measures; Medical; Medical Care Team; Medical Genetics; Minor; Molecular Diagnosis; North America; Operative Surgical Procedures; Outcome; Parents; Pathology; Pathway interactions; Patient Care; Patients; Persons; Phenotype; Physiological; Population; Positioning Attribute; Procedures; Process; Protocols documentation; Proxy; Quality of life; Quality-of-Life Assessment; Recommendation; Records; Registries; Reporting; Research; Research Design; Research Infrastructure; Research Personnel; Resources; Sampling; Scientist; Sequence Analysis; Sexual Development; Site; Standardization; Time; Translational Research; Translations; Treatment Protocols; Uncertainty; Uterus; Variant; base; behavioral health; cancer risk; clinical care; clinical practice; design; evidence base; experience; genital surgery; health care delivery; health related quality of life; improved; indexing; insight; male; malformation; multidisciplinary; novel; patient registry; prospective; psychologic; psychosocial; research and development; sex; sex development disorder; skills; social; success; tool

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.

描述（由申请人提供）：性发育障碍（DSD）具有不同的表型，范围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。总体而言，DSD 的发病率估计约为 1%。 DSD 可能会对行为健康、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，患有 DSD 的孩子的出生以及随之而来的未来心理和性发育的不确定性被认为是异常紧张的。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。然而，关于患者结果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，妨碍精确的诊断分类，以及缺乏对健康和生活质量结果的前瞻性纵向研究。 该提案为基于假设的性发育机制研究以及为受 DSD 影响的患者和家庭提供循证护理提供了一个平台。目标 1 通过特定 DNA 捕获和测序、拷贝数变异分析以及 DSD 新候选基因鉴定的逐步方法，确定性发育的新遗传机制，并提高对 DSD 病理生理学和分子诊断的理解。目标 2 为多个研究地点和研究者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 通过使用综合心理社会和健康相关的生活质量评估电池来确定短期和中期结果 适用于常规临床护理的强有力的心理测量措施，是制定基于证据的心理社会治疗方案的必要步骤。目标 4 建立可持续的研究基础设施，并通过整合标准化 DSD 诊断和治疗方案并促进跨网络站点的医疗保健提供最佳实践的转移，确保将新证据快速转化为持续的临床实践。该注册中心提供了一个分析平台，用于在研究人员和研究中心之间收集、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地点转变为自我维持的 DSD 临床护理“卓越中心”，同时登记册作为假设驱动研究的关键资源，具有附加值。

项目成果

Disorders of sex development (DSD): Clinical service delivery in the United States.

• DOI: 10.1002/ajmg.c.31558
• 发表时间: 2017-06
• 期刊: American journal of medical genetics. Part C, Seminars in medical genetics
• 作者: Rolston AM;Gardner M;van Leeuwen K;Mohnach L;Keegan C;Délot E;Vilain E;Sandberg DE;members of the DSD-TRN Advocacy;Advisory Network Accord Alliance
• 通讯作者: Advisory Network Accord Alliance

University of Michigan disorders of sex development (DSD) research and quality improvement symposium.

密歇根大学性发育障碍（DSD）研究和质量改进研讨会。

• DOI: 10.1007/978-1-4419-8002-1_34
• 发表时间: 2011
• 期刊: Advances in experimental medicine and biology
• 作者: Sandberg,DavidE;Asciutto,AnthonyJ;Haddad,Emily
• 通讯作者: Haddad,Emily

Parenting Children with Disorders of Sex Development (DSD): A Developmental Perspective Beyond Gender.

养育患有性发育障碍（DSD）的孩子：超越性别的发展视角。

• DOI: 10.1055/s-0034-1398561
• 发表时间: 2015
• 期刊: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
• 作者: Wisniewski,AB;Sandberg,DE
• 通讯作者: Sandberg,DE

Disorders of Sex Development: Why Adolescent Medicine Specialists Should Care.

性发育障碍：为什么青少年医学专家应该关心。

• 发表时间: 2015
• 期刊: Adolescent medicine: state of the art reviews
• 作者: Sandberg,DavidE

Hurdling over sex? Sport, science, and equity.

跨越性？

• DOI: 10.1007/s10508-014-0332-0
• 发表时间: 2014
• 期刊: Archives of sexual behavior
• 影响因子: 3.8
• 作者: Ha,NathanQ;Dworkin,ShariL;Martínez-Patiño,MaríaJosé;Rogol,AlanD;Rosario,Vernon;Sánchez,FranciscoJ;Wrynn,Alison;Vilain,Eric
• 通讯作者: Vilain,Eric