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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Intramural Research (Z01)
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National Institute on Aging
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Milhorat, Thomas H; Bolognese, Paolo A; Nishikawa, Misao et al. (2007) Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and chiari malformation type I in patients with hereditary disorders of connective tissue. J Neurosurg Spine 7:601-9
Liberfarb, Ruth M; Levy, Howard P; Rose, Peter S et al. (2003) The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med 5:21-7
Wenstrup, Richard J; Meyer, Richard A; Lyle, Jennifer S et al. (2002) Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med 4:112-7
Ho, Nicola C; Hadley, Donald W; Jain, Pawan K et al. (2002) Case 47: dural ectasia associated with Marfan syndrome. Radiology 223:767-71
Rose, P S; Ahn, N U; Levy, H P et al. (2001) Thoracolumbar spinal abnormalities in Stickler syndrome. Spine (Phila Pa 1976) 26:403-9
Szymko-Bennett, Y M; Mastroianni, M A; Shotland, L I et al. (2001) Auditory dysfunction in Stickler syndrome. Arch Otolaryngol Head Neck Surg 127:1061-8
Peters, K F; Kong, F; Horne, R et al. (2001) Living with Marfan syndrome I. Perceptions of the condition. Clin Genet 60:273-82
Peters, K F; Horne, R; Kong, F et al. (2001) Living with Marfan syndrome II. Medication adherence and physical activity modification. Clin Genet 60:283-92
Rose, P S; Ahn, N U; Levy, H P et al. (2001) The hip in Stickler syndrome. J Pediatr Orthop 21:657-63