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 200 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. A manuscript describing these findings is in preparation. ? 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 submitted. The summary of spine findings 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. These findings will be presented at the ASHG 2006 meeting, and manuscripts are being prepared.? 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 will be pursued 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 in the last year. 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 with this syndrome, and whole genome scans are planned on the DNA samples when all the subjects have been enrolled in the upcoming year. The identification of this syndrome will be presented at the 2006 ASHG as a platform presentation.? Mutational analysis of the COL2A1 and COL11A1 genes for thirty nine subjects with Stickler syndrome has been completed and twenty novel mutations have been identified. A poster describing the genotype/phenotype correlations will be presented at ASHG 2006, and a manuscript is in preparation. We plan the sequence the CSPG2 gene in the remaining 19 patients. This gene was recently implicated in the closely related Wagner syndrome and it is a strong candidate gene for Stickler syndrome patients without COL2A1 and COL11A1 mutations. If mutations in CSPG2 are identified, this opens the door for potential treatment of Stickler syndrome by targeting the pathway involved.? 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.? 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.
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