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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
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