Hereditary Disorders Of Connective Tissue--Clinical And Molecular Studies

本研究考察了结缔组织遗传性疾病的临床和分子效应，包括马凡综合征、埃勒斯-丹洛斯综合征(EDS)和斯蒂克勒综合征，以及相关疾病，如家族性动脉瘤综合征和纤维肌肉发育不良。到目前为止，大约有350名受试者参加了这项研究。这项研究的纵向臂纳入了年龄在12岁及以上的受试者，并收集了每个参与者的详细心血管信息，包括超声心动图、心电图、24小时Holter检查和脉搏波速度数据。对Ehler-Danlos综合征患者的超声心动图分析显示，在这组患者中，主动脉根部扩张的发生率为30%，一篇手稿已经发表，描述了这一组患者以前未被承认的发现，包括左心室松弛受损、心脏轮廓延长、右冠状动脉突出和肺压力升高的发生率增加。根据动态心电图数据的频域分析和立位血压测量，30%的EDS受试者有自主神经功能障碍并伴有交感神经张力增加和体位性直立性心动过速(POTS)。目前正在对这些数据进行分析。骨密度测定研究表明，骨质疏松症和骨量减少在EDS和马凡人群中非常常见，可能与特定的突变有关。颈椎和腰椎的MRI研究也收集了受试者的数据。我们最近发现，大约三分之一的患者有Chiari I型畸形，超过85%的受试者有明显的脊柱异常，包括椎间盘突出、腰椎滑脱、硬膜扩张。描述Chiari I畸形与结缔组织遗传性疾病的关联的手稿已经被接受。总结这项研究结果的11个摘要将作为平台展示在即将到来的美国人类遗传学学会(ASHG)年会上。我们注意到以前未被发现的EDS并发症，包括患有EDS的老年人(在我们的队列中占15%)发生类风湿性关节炎，临床上显著的睡眠障碍的发生率增加，以及与包括青少年EDS队列在内的所有年龄组的NHANES平均水平相比，不良血脂谱的高患病率。我们还在分析队列中胃肠和内分泌异常的数据。我们发现了一种家族性动脉瘤综合征，其特征类似于马凡综合征、斯蒂克勒综合征和埃勒斯-丹洛斯综合征。受影响的患者除主动脉瘤外，还有关节活动过度、眼部视网膜脱离或玻璃体变性，以及轻微的头面部和骨骼特征。已确认来自两个家庭的21名患者，并在Illumina平台上完成了6000个SNP的连锁分析。结果表明，有四个地区的LOD得分较高。这些区域的序列分析正在进行中，以确定致病突变。以前的连锁分析没有发现与引起家族性动脉瘤综合征或结缔组织疾病的已知区域的连锁，因此很有可能在这两个家族中发现一个新的基因。一种以前未被认识的结缔组织遗传性疾病，纤维肌肉发育不良(FMD)，具有结缔组织特征，已在参与研究的受试者中被发现。这组患者除了关节活动过度、高度近视、异常疤痕和皮肤高度伸展外，还有颈动脉、肾动脉、脑或冠状动脉的FMD。已经确定了大约50名患者，并在2006年ASHG上作为平台展示了研究结果。一项与安迪·辛格尔顿合作的全基因组扫描研究正在进行中，以确定相关基因。我们还在筛选先天性肾上腺增生症患者的DNA样本，以检测Tenascin X(TNX)基因的缺失。该基因位于编码21-羟基酶的CYP21基因附近的高度可变的RCCX模块中，已被认为是高运动型EDS患者的致病基因。约30%的CAH患者有较大的CYP21缺失，并怀疑其中许多缺失延伸至TNX。在一些患者中观察到关节过度活动和异常瘢痕形成，我们正在调查TNX缺失与这些发现的临床相关性。除了常见的缺失外，去年在CAH队列中还发现了新的突变和缺失。 这项研究的最终目标是开发治疗结缔组织遗传性疾病的并发症和发病率的策略，其中最重要的是动脉瘤破裂和夹层。目前正在努力利用从受影响患者那里获得的成纤维细胞培养来研究和改变这些并发症所涉及的途径，如TGFb途径。成纤维细胞适合于这种方法，因为所涉及的基因具有高水平的表达，所涉及的疾病中频繁的皮肤异常就证明了这一点，而且可以很容易地从受影响的受试者那里以微创的方式获得皮肤活检。此外，与心血管科学实验室的Talan博士和约翰霍普金斯医疗机构的Dietz博士的合作重点是利用血管EDS的小鼠模型来开发治疗策略。

This study examines the clinical and molecular effects of heritable disorders of connective tissue including Marfan syndrome, Ehlers-Danlos syndrome (EDS) and Stickler syndrome, as well as related disorders such as familial aneurysm syndromes and fibromuscular dysplasia. To date, approximately 350 subjects have been enrolled in the study. The longitudinal arm of the study enrolls subjects 12 years and above, and detailed cardiovascular information including echocardiograms, ECG, a 24 hour Holter study, and pulse wave velocity data is collected on each participant. Echocardiography analysis of patients with Ehlers-Danlos syndrome demonstrated a 30% incidence of aortic root dilation in this group of patients and a manuscript has been published describing previously unrecognized findings in this group of patients including impaired left ventricular relaxation, elongated cardiac silhouette, prominence of the right coronary artery, and increased incidence of elevated pulmonary pressures. Autonomic dysfunction with increased sympathetic tone and Postural Orthostatic Tachycardia (POTS) has been documented in 30% of the subjects with EDS, based on frequency domain analysis of the Holter data as well as orthostatic blood pressure measurements. This data is currently being analyzed. Bone densitometry studies have shown osteoporosis and osteopenia are very common in the EDS and Marfan populations, and may be correlated with specific mutations. MRI studies of the cervical and lumbar spine are also collected on subjects. We have recently identified that approximately one third of patients have Chiari I malformations and more than 85% of the subjects have significant abnormalities pertaining to the spine including hernitated discs, spondylolisthesis, dural ectasia. A manuscript describing the association of Chiari I malformation with hereditary disorders of connective tissue has been accepted. Eleven abstracts summarizing findings from the study will be presented at the upcoming American Society of Human Genetics (ASHG) annual meeting as a platform presentation. We have noted previously unrecognized complications of EDS, including the development of rheumatoid arthritis in older persons with EDS (in 15% of our cohort), increased incidence of clinically significant sleep disorders, and a high prevalence of unfavorable lipid profiles as compared to NHANES averages in all age groups including the teenage EDS cohort. We are also analyszing data on gastrointestinal and endocrine abnormalities in the cohort. We have identified a familial aneurysm syndrome with features resembling Marfan syndrome, Stickler syndrome and the Ehlers-Danlos syndrome. Affected persons have joint hypermobility, retinal detachments or vitreous degeneration in the eye, and mild craniofacial and skeletal features in addition to aortic aneurysm. Twenty one affected persons from two families have been identified and a 6000-SNP linkage analysis has been completed on the Illumina platform. The results indicate four regions with high LOD scores. Sequence analysis of these regions is ongoing in order to identify the causative mutation. Previous linkage analysis were negative for linkage to known regions that cause familial aneurysm syndromes or connective tissue disorder, so it is highly likely that a novel gene will be identified in these two families. A previously unrecognized hereditary disorder of connective tissue, fibromuscular dysplasia (FMD) with connective tissue features has been identified within subjects enrolled in the study. This group of patients have FMD of carotids, renal arteries, brain or coronary vessels, in addition to hypermobile joints, high myopia, abnormal scarring, and hyperextensible skin. Approximately fifty patients have been identified, and findings were presented at the 2006 ASHG as a platform presentation. A whole genome scan study is ongoing to identify associated genes in collaboration with Andy Singleton. We are also in the process of screening DNA samples from patients Congenital Adrenal Hyperplasia for deletions of the Tenascin X (TNX) gene. This gene lies in the hypermutable RCCX module near the CYP21 gene encoding 21-hydroxylase, and has been implicated as a causative gene in patients with the hypermobile form of EDS. Approximately 30% of patients with CAH have large CYP21 deletions and it is suspected that many of them have deletions extending into TNX. Joint hypermobility and abnormal scarring has been observed in some of the patients, and we are investigating the clinical correlation of TNX deletions with these findings. Novel mutations and deletions have been identified in the CAH cohort in the last year, in addition to the common deletion. The ultimate goal of the study is to develop strategies for the treatment of complications and morbidities of hereditary disorders of connective tissue, most significant of which are ruptured aneurysms and dissections. Efforts are underway utilizing fibroblast cultures obtained from affected patients to study and alter the pathways involved in these complications, such as the TGFB pathway. Fibroblasts are suitable for this approach since the genes involved have high levels of expression as evidenced by frequent skin abnormalities in the disorders involved, and a skin biopsy can be readily obtained in a minimally invasive fashion from affected subjects. In addition, collaborative work with Dr. Talan from Laboratory of Cardiovascular Science and Dr. Dietz at Johns Hopkins Medical Institutions is focused on utilizing a mouse model of vascular EDS in developing treatment strategies.