Hereditary Disorders Of Connective Tissue

本研究探讨了三个著名的结缔组织遗传性疾病，马凡氏综合征，Ehlers-Danlos综合征和Stickler综合征的临床和分子效应。在过去的几年中，在NIH临床中心共观察到约80名患有三种特定诊断的患者和40名患有重叠疾病的参与者。收集了所有280名参与者的自然病史数据，包括眼科、耳鼻喉科、超声心动图和康复医学咨询。我们的研究记录了这些疾病的新认识的胃肠道并发症，慢性肌肉骨骼疼痛是EDS和Stickler综合征的重要并发症。对Ehlers-Danlos综合征患者的超声心动图分析表明，该组患者的主动脉根部扩张发生率为30%。我们比较了柏林和根特的马凡氏综合征疾病分类，并检查了硬脑膜扩张筛查在诊断马凡氏综合征中的有效性。我们分析了Stickler综合征中脊柱和髋关节异常的患病率及其与慢性疼痛的关系。我们的研究证实Stickler综合征患儿股骨头衰竭的风险增加。我们已经制定了建议的诊断标准Stickler综合征的基础上，我们的临床和分子研究，在这一人群。描述这些标准的手稿目前正在印刷中。我们已经确定了一个以前未描述的结缔组织疾病的特点类似马凡综合征，Stickler综合征和Ehlers-Danlos综合征。 在过去的一年中，我们已经招募了100多名被诊断为Ehlers-Danlos，Marfan或Stickler综合征的受试者，以及新认识的表型，包括所有这三种疾病的特征。所有受试者均进行了详细的病史和体格检查、常规血液化学和血液学评价、循环骨标志物、超声心动图、骨密度测定、霍尔特监测、EKG、胸腹主动脉和腰椎MRI。他们还完成了关于疼痛，生活质量和睡眠的广泛问卷调查。 慢性肌肉骨骼疼痛是许多遗传性结缔组织疾病的严重并发症。在Ehlers-Danlos综合征中尤其如此，我们的问卷记录了这一印象。我们发现Ehlers-Danlos综合征的参与者确实有轻度的主动脉扩张，正如以前报道的那样。这些患者也有突出的右冠状动脉，以前未报告的发现。一些受试者有轻度骨密度降低和身体成分异常，需要进一步研究。我们还发现霍尔特监测异常提示植物神经功能紊乱。一些患者已经表现出循环骨标志物的异常。过去新研究的临床参数包括反射波研究，以使用气体放电可视化装置观察颈动脉血管硬度和整体活力水平。目前正在进行分子遗传学研究，以确定先前识别的基因中的突变。不能发现已知基因突变的家庭将扩大连锁分析，试图确定新认识的基因引起这些疾病。

This study examines the clinical and molecular effects of three well-known heritable disorders of connective tissue, Marfan syndrome, Ehlers-Danlos syndrome and Stickler syndrome. During previous years, a total of approximately 80 patients with each of the three specific diagnoses and 40 participants with an overlap disorder were seen in the NIH Clinical Center. Natural history data have been collected on all 280 participants, including ophthalmologic, otolaryngologic, echocardiography and rehabilitation medicine consultations. Our studies have documented newly recognized gastrointestinal complications of these disorders, and that chronic musculoskeletal pain is a significant complication of both EDS and Stickler syndrome. Echocardiography analysis of patients with Ehlers-Danlos syndrome demonstrated a 30% incidence of aortic root dilation in this group of patients. We have compared the Berlin and Gent nosologies for the Marfan syndrome in our population and examined the efficacy of screening for dural ectasia in the diagnosis of the Marfan syndrome. We have analyzed the prevalence of spinal and hip abnormalities in Stickler syndrome and their relationship to chronic pain. Our studies documented an increased risk of femoral head failure in children with Stickler syndrome. We have developed proposed diagnostic criteria for Stickler syndrome based on our clinical and molecular studies in this population. A manuscript describing these criteria is currently in press. We have identified a previously undescribed connective tissue disorder with features resembling Marfan syndrome, Stickler syndrome and the Ehlers-Danlos syndrome. In the last year we have enrolled over 100 subjects with the diagnoses of Ehlers-Danlos, Marfan or Stickler syndrome, as well as a newly recognized phenotype including features of all three of these disorders. All the subjects have had detailed history and physical examinations, routine blood chemistry and hematology evaluations, circulating bone markers, echocardiogram, bone densitometry, Holter monitoring, EKG, MRI of the thoracic and abdominal aorta and the lumbar spine. They also completed extensive questionnaires about pain, quality of life and sleep. Chronic musculoskeletal pain is a serious complication of many of the hereditary disorders of connective tissue. This is particularly true in the Ehlers-Danlos syndrome, and our questionnaires are documenting this impression. We are finding that participants with Ehlers-Danlos syndrome do have mild aortic dilation, as previously reported. These patients also have prominence of the right coronary artery, a previously unreported finding. Some of the subjects have mildly reduced bone density and abnormalities of body composition that will require further investigation. We are also finding abnormalities on Holter monitoring suggestive of autonomic dysfunction. Some of the patients have demonstrated abnormalities of circulating bone markers. Newly investigated clinical parameters during the past include the reflected wave study to look at carotid vessel stiffness and overall levels of vitality using the Gas Discharge Visualization device. Molecular genetic studies to identify mutations in previously recognized genes, are underway. Families in which mutations in known genes cannot be found will be expanded for linkage analysis in an attempt to identify newly recognized genes causing these disorders.