The purpose of this study is to examine cardiovascular and musculoskeletal complications of heritable connective tissue disorders (HDCT) and the natural history of these complications.

The purpose of this research is to investigate a group of genetic disorders called the Hereditary Disorders of Connective Tissue and describe the health problems associated with these conditions. These disorders and their prominent symptoms include:

• Marfan Syndrome--vascular dilatation (enlargement) and dissection (a tear in the lining), skeletal abnormalities
• Ehlers-Danlos Syndrome--soft fragile skin, bleeding problems, joint laxity (looseness), chronic pain
• Stickler Syndrome--premature osteoarthritis, bifid uvula (a split in the fleshy lobe hanging down from the soft palate), cleft palate, hearing loss, vitreoretinal degeneration (degeneration of the retina and the transparent gel that fills the inner portion of the eyeball between the lens and the retina)

People who have a known or strongly suspected diagnosis are eligible to participate. At the NIA ASTRA unit at Harbor Hospital, a study investigator will obtain a detailed medical history and perform a physical examination on participants. These evaluations will occur every 2 years for 5 years. Additional studies may include an echocardiogram, ECG, Holter study, bone densitometry, blood and urine tests, magnetic resonance imaging (MRI)/MRA studies and vascular studies. A skin biopsy may be done with a separate consent for some participants. Questionnaires about pain and quality of life will be completed by participants.

• Ehlers-Danlos Syndrome
• Marfan Syndrome
• Stickler Syndrome

• Longitudinal Study Arm: 450 participants who will be involved in extensive testing and will be followed longitudinally. Each participant spends approximately 2 days undergoing clinical evaluations. The clinical visits occur every 1 to 5 years based on the subject's age, medical condition, and ability to travel to the study location.
• Mutational Analysis Arm: There is an upper limit of 1385 participants for this arm. Participants may come to the NIA Clinical Research Unit for a one-time visit (less than one day in length), or they may enroll off-site by sending in bloods, saliva, or bucca samples for the DNA analysis.
• Genome Protocol Arm: This arm consists of participants who have been previously enrolled under NHGRI protocol 97-HG-0089, presently inactive. The samples are housed at NIA facilities for use by the PI and collaborators approved by the NIA IRB.

• Ainsworth SR, Aulicino PL. A survey of patients with Ehlers-Danlos syndrome. Clin Orthop. 1993 Jan;(286):250-6.
• Beighton P, de Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R, Hall JG, Hollister DW, Horton W, McKusick VA, et al. International Nosology of Heritable Disorders of Connective Tissue, Berlin, 1986. Am J Med Genet. 1988 Mar;29(3):581-94. No abstract available.
• Dietz HC, Pyeritz RE, Hall BD, Cadle RG, Hamosh A, Schwartz J, Meyers DA, Francomano CA. The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3. Genomics. 1991 Feb;9(2):355-61.
• Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991 Jul 25;352(6333):337-9.
• Francomano CA, Liberfarb RM, Hirose T, Maumenee IH, Streeten EA, Meyers DA, Pyeritz RE. The Stickler syndrome: evidence for close linkage to the structural gene for type II collagen. Genomics. 1987 Dec;1(4):293-6.
• Francomano CA, Liberfarb RM, Hirose T, Maumenee IH, Streeten EA, Meyers DA, Pyeritz RE. The Stickler syndrome is closely linked to COL2A1, the structural gene for type II collagen. Pathol Immunopathol Res. 1988;7(1-2):104-6. No abstract available.

Inclusion Criteria:

• Established or strongly suspected diagnosis of Ehlers-Danlos, Marfan, or Stickler syndrome within immediate family
• Personal or family history of one or more of the following features in a pattern suggestive of a heritable connective tissue disorder: Marfanoid body habitus (unusually long limbs and digits, deformation of the chest wall), aortic dilatation and/or dissection (a large vessel that comes out of the heart), aneurysms (balloon shaped enlargements) in other vessels, ectopia lentis (dislocation of the lens of the eye), detached retina (separation of the retina from the eyeball), vitreous degeneration (degeneration of the gel that fills the eye) and/or early onset high myopia (near-sightedness), cleft palate, joint laxity and/or dislocation, premature osteoarthritis, skin fragility, striae (stretch marks), easy bruising, and/or hyperextensible skin, scoliosis (curvature of the spine), spondylolisthesis (slippage of the bones of the spine) and/or dural ectasia (distortion of the lining of the spinal cord), high frequency sensorineural hearing loss (inability to hear certain sounds due to nerve impairment)

Exclusion Criteria:

• Inability to provide informed consent
• Pregnant and nursing women may be limited in their participation in some aspects of the study (e.g. ionizing radiation exposure or MRI) during the time that they are pregnant or nursing