Natural History Study of Patients with Excess Androgen

我们招募的患者仍然非常出色，代表了有史以来在一个中心看到的最大的CAH和FMPP患者队列。迄今为止，我们已经招募了400多名CAH患者和15名FMPP患者。 对21-羟化酶缺乏引起的CAH患者进行了全面的临床表型分析。详细的临床评价显示，转诊患者的治疗方法差异很大，尤其是在成人中，只有30%的患者在可接受的疾病控制的基础上肾上腺激素。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是常见的。正在进行进一步的研究，探索这些不良后果。 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在CAH的管理中很重要，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CYP 21 A2定位于HLA复合体内6号染色体的短臂（6p21.3）。 该位点的高遗传变异率、CYP 21 A2基因重复的存在以及CYP 21 A1 P假基因的存在使疾病和携带者状态的确定复杂化。 在我们的大型21-羟化酶缺乏症CAH患者队列中，我们报告了广泛使用的基于PCR的CYP 21 A2分析，针对最常见的突变，未能在10%的患者中识别突变，比预期的要多。 我们还发现，不寻常的重复CYP 21 A2单倍型有时会干扰基因分型，并可能导致商业实验室报告的错误结果。此外，我们发现大基因缺失的连接位点分析与临床相关，可以解释为什么一些大缺失患者具有轻度表型。 一个重要的并行项目是评估与表型相关的邻近基因。 我们描述了一种新的CAH-Tenascin X连续体基因缺失综合征，称为CAH-X综合征。腱生蛋白-X缺陷，以隐性或显性形式，已被提出作为高活动性型埃勒斯-当洛斯综合征（EDS）的原因。 在第一次系统研究CAH患者中的腱生蛋白缺乏症时，我们发现193名连续的无关CAH患者中有14名（7%）患有新的CAH-X综合征。我们随后发现了一种新的嵌合基因作为CAH-X的病因，扩大了这种综合征的范围。 现在估计大约有10%的CAH患者受到CAH-X的影响。 我们还描述了CAH-X中TGF-β通路的失调。进一步的研究正在进行中，以更好地确定这种新的CAH-X综合征的临床，分子和生化方面。

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 over 400 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 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. An important concurrent project is the evaluation of neighboring genes in relation to phenotype. We described a novel CAH-Tenascin X Contiguous Gene Deletion Syndrome, 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. We subsequently identified a novel chimeric gene as a cause of CAH-X, broadening the spectrum of this syndrome. Approximately 10 percent of CAH patients are now estimated to be affected by CAH-X. We also described TGF-beta pathway dysregulation in CAH-X. Further studies are underway to better define the clinical, molecular and biochemical aspects of this novel CAH-X syndrome.