Natural History Study of Patients with Excess Androgen

雄激素过多患者的自然史研究

• 批准号: 8941566
• 负责人: Deborah Merke
• 金额: $ 2.47万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8941566
• 关键词: 6p21.3; Adrenal Gland Neoplasms; Adrenal gland hypofunction; Adrenal hormone preparation; Adult; Androgens; Biochemical; Bone Density; CYP21A2 gene; Child; Childhood; Chromosomes, Human, Pair 6; Clinical; Cognition; Collaborations; Complex; Congenital adrenal hyperplasia; Diagnosis; Disease; Ehlers-Danlos Syndrome; Emotional; Enrollment; Etiology; Evaluation; Future; Gene Deletion; Gene Duplication; Genes; Genetic; Genetic Counseling; Genotype; Growth; Growth and Development function; Haplotypes; Hormonal; Hyperandrogenism; Knowledge; Laboratories; Maps; Measurement; Mediating; Metabolic; Methodology; Molecular; Mutation; Natural History; Neonatal Screening; Patient Recruitments; Patients; Phenotype; Precocious Puberty; Protocols documentation; Pseudogenes; Puberty; Quality of life; Reporting; Research Personnel; Scientist; Site; Steroid 21-Monooxygenase; Syndrome; Tenascin; Testicular Neoplasms; Therapeutic Intervention; Variant; adverse outcome; arm; base; cardiovascular risk factor; carrier status; clinical phenotype; clinically relevant; cohort; design; disorder control; genetic analysis; male; memory process; novel; premature; programs; psychologic; research clinical testing; tenascin X

Our recruitment of patients continues to be excellent and represents the largest cohort of CAH and FMPP patients ever seen at one center. To date, we have enrolled 350 patients with CAH, and 15 patients with FMPP. Comprehensive clinical phenotyping of patients with CAH due to 21-hydroxylase deficiency has been performed. Detailed clinical evaluations reveal great variation in treatment approaches of referred patients, especially amongst adults, with only 30% of patients in acceptable disease control based on adrenal hormones. Adult short stature, abnormal growth and development of children, cardiovascular risk factors, reduced bone mineral density and adrenal and testicular tumor formation are common. Further studies exploring these adverse outcomes are underway. Patients with CAH and other forms of adrenal insufficiency have been reported to have poor quality-of-life. Cognition, emotional processing, memory and quality-of-life is being evaluated. Genotyping and genetic counseling are important in the management of CAH, and genotyping has been suggested as a potential second tier screen to hormonal measurements in neonatal screening programs. The gene encoding 21-hydroxylase, CYP21A2, is mapped to the short arm of chromosome 6 (6p21.3) within the HLA complex. The high rate of genetic variability at this locus, the presence of CYP21A2 gene duplications, and the presence of the CYP21A1P pseudogene complicate the determination of disease and carrier status. In our large cohort of patients with CAH due to 21-hydroxylase deficiency, we reported that the widely used PCR-based CYP21A2 analysis that targets most common mutations failed to identify mutations in 10 percent of our patients, more often than expected. We also found that unusual duplicated CYP21A2 haplotypes sometimes interferes with genotyping and may result in erroneous results reported by commercial laboratories. In addition, we recently found that junction site analysis of large gene deletions is clinically relevant and can explain why some patients with large deletions have a mild phenotype. Our findings to date have broad implications in the use of genetic analysis in the diagnosis and management of CAH. We are currently comparing various methodologies and aim to establish a suggested protocol for performing CYP21A2 genetic analysis and incorporating genetic analysis into the management of CAH. An important concurrent project is the evaluation of neighboring genes in relation to phenotype. In collaboration with scientists from NIA, we are evaluating a novel CAH-Tenascin X Contiguous Gene Deletion Syndrome, we termed CAH-X Syndrome. Tenascin-X deficiency, in recessive or dominant form, has been proposed as a cause of hypermobility type Ehlers-Danlos Syndrome (EDS). In the first ever systematic study tenascin deficiency in CAH patients, we found that 14 (7 percent) of 193 consecutive unrelated CAH patients have the novel CAH-X Syndrome. Further studies are underway to better define the clinical, molecular and biochemical aspects of this novel CAH-X syndrome.

我们的患者招募工作仍然非常出色，是一个中心有史以来规模最大的 CAH 和 FMPP 患者群体。迄今为止，我们已入组 350 名 CAH 患者和 15 名 FMPP 患者。 已对 21-羟化酶缺乏所致 CAH 患者进行了全面的临床表型分析。详细的临床评估显示，转诊患者的治疗方法存在很大差异，尤其是在成人中，只有 30% 的患者基于肾上腺激素的疾病控制处于可接受的水平。成人身材矮小、儿童生长发育异常、心血管危险因素、骨密度降低以及肾上腺和睾丸肿瘤形成都很常见。探索这些不良后果的进一步研究正在进行中。 据报道，CAH 和其他形式的肾上腺功能不全患者的生活质量较差。认知、情绪处理、记忆和生活质量正在接受评估。 基因分型和遗传咨询对于 CAH 的治疗非常重要，并且基因分型已被建议作为新生儿筛查计划中激素测量的潜在第二层筛查。 编码 21-羟化酶的基因 CYP21A2 被映射到 HLA 复合体中 6 号染色体的短臂 (6p21.3)。 该位点的高遗传变异率、CYP21A2 基因重复的存在以及 CYP21A1P 假基因的存在使疾病和携带者状态的确定变得复杂。 在我们因 21-羟化酶缺乏而导致的 CAH 患者的大型队列中，我们报告说，广泛使用的基于 PCR 的 CYP21A2 分析针对最常见的突变，未能识别 10% 的患者的突变，这一比例高于预期。 我们还发现，不寻常的重复 CYP21A2 单倍型有时会干扰基因分型，并可能导致商业实验室报告错误的结果。此外，我们最近发现大基因缺失的连接位点分析具有临床相关性，并且可以解释为什么一些大缺失的患者具有轻度表型。 迄今为止，我们的研究结果对于遗传分析在 CAH 的诊断和治疗中的应用具有广泛的意义。 我们目前正在比较各种方法，旨在建立一个执行 CYP21A2 遗传分析并将遗传分析纳入 CAH 管理的建议方案。 一个重要的并发项目是评估与表型相关的邻近基因。 我们与 NIA 的科学家合作，正在评估一种新型 CAH-Tenascin X 连续基因缺失综合征，我们将其称为 CAH-X 综合征。隐性或显性形式的腱蛋白-X 缺陷已被认为是过度活动型埃勒斯-当洛斯综合征 (EDS) 的原因。 在第一项针对 CAH 患者生腱蛋白缺乏症的系统研究中，我们发现 193 名连续的不相关 CAH 患者中有 14 名（7%）患有新型 CAH-X 综合征。进一步的研究正在进行中，以更好地定义这种新型 CAH-X 综合征的临床、分子和生化方面。