Natural History Study of Patients with Excess Androgen

我们招募的患者仍然很出色，是有史以来在一个中心看到的最大规模的CAH和FMPP患者队列。到目前为止，我们已经招募了400多名CAH患者和15名FMPP患者。 对21-羟基酶缺乏所致的CAH患者进行了全面的临床表型。详细的临床评估显示，转诊患者的治疗方法差异很大，特别是在成年人中，只有30%的患者基于肾上腺激素进行了可接受的疾病控制。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的形成是常见的。探索这些不良后果的进一步研究正在进行中。 据报道，患有CAH和其他形式的肾上腺功能不全的患者的生活质量较差。正在对认知、情绪处理、记忆和生活质量进行评估。 基因分型和遗传咨询在CAH的治疗中很重要，基因分型已被认为是新生儿筛查项目中激素测量的潜在二级筛查方法。编码21-羟基酶的基因CYP21A2被定位在人类白细胞抗原复合体内6号染色体(6p21.3)的短臂上。该基因座的遗传变异率高，存在CYP21A2基因重复，以及存在假基因，使疾病和携带者状态的确定变得复杂。 在我们因21-羟基酶缺乏而导致的CAH患者中，我们报告了广泛使用的基于PCR的针对最常见突变的CYP21A2分析未能在10%的患者中发现突变，这比预期的情况要频繁得多。我们还发现，不寻常的重复的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的错误结果。此外，我们发现大基因缺失的连接位点分析在临床上是相关的，并可以解释为什么一些大基因缺失的患者具有轻微的表型。 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邻近基因缺失综合征，称为CAH-X综合征。以隐性或显性形式存在的Tenascin-X缺乏症被认为是多动型Ehler-Danlos综合征(EDS)的原因之一。在有史以来第一次对CAH患者进行的系统研究中，我们发现连续193名无关的CAH患者中有14名(7%)患有新的CAH-X综合征。我们随后发现一个新的嵌合基因是CAH-X的原因，拓宽了这种综合征的谱系。据估计，大约10%的CAH患者现在受到CAH-X的影响。我们还描述了转化生长因子-β途径在CAH-X中的失调。进一步的研究正在进行中，以更好地确定这种新型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.