The Ehlers Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue characterized by joint, skin and vascular abnormalities. Vascular dissections and aneurysms are a cardinal feature of the vascular form of EDS (VEDS) caused by mutations in COL3A1. Loeys-Dietz syndrome, a closely related phenotype, is caused by mutations in TGFbetaR2 or TGFbetaR1. We have identified a group of patients without mutations in COL3A1, TGFbetaR2 or TGFbetaR1 who presented with dissections and aneurysms as well as stenotic lesions with a diagnosis of fibromuscular dysplasia (FMD) by pathology or radiology. Varying features of EDS such as atrophic scars, velvety or stretchy skin, joint hypermobility as evidenced by a high Beighton score, history of articular dislocations, uterine prolapse, joint pain, pectus deformities, pes planus and scoliosis were also present. Several of the patients had a family history of premature death from vascular events, as well as a family history of joint and skin abnormalities compatible with an autosomal dominant inheritance pattern. The etiology of FMD is thought to be heterogeneous, with genetic and environmental factors proposed as possible contributors. Our findings suggest that there is a distinct variant of EDS, separate from the VEDS and Loeys-Dietz syndrome, with FMD as a clinical feature in addition to the skin and joint abnormalities. Given the similarities with the disorders caused by mutations in receptors of TGFbeta, the hypothesis was entertained that FMD is caused by germline mutations in another gene in the same pathway. Derangements of the TGFbeta pathway were investigated in the FMD patients using direct tissue immunochemical approach in collaboration with Dr. Bart Loeys. Increased levels of pSMAD2 was seen in a subset of patient samples. The results pertaining to the TGFbeta pathway are being verified utilizing Western blotting techniqueds in fibroblast lines. To identify gene(s) that are associated with the FMD phenotype, an initial cohort of 60 patients with FMD was identified and enrolled in protocol 2003-086, and a whole genome association study was completed in collaboration with, Dr. Singleton using the Illumina Platform with HumanCNV370-Duo BeadChips and HumanHap550 BeadChips. The results indicate linkage to multiple regions 1p35.3, 3q24, 3q28, 5p14.3, 6p25.3, 8p23.2, 10p12.1, 12q13.13, 17q21.2, and 18p11.22. Based on the initial results, it was estimated that 90 additional samples would serve to narrow down the linkage regions. The patient recruitment is now complete and the second phase of the whole genome association is underway. We have also actively investigated biomarkers of disease activity in plasma samples from FMD patients with FMD and have compared these results to unaffected controls and to patients affected with other disorders such as Marfan syndrome and Vascular EDS in collaboration with Dr. Jennifer Van Eyk. Initial results indicate that CRP, iCAM and vCAM are significantly elevated in FMD as compared to controls. Serum Amyloid Alpha (SAA) shows correlations with disease activity. Circulating TGFbeta1 levels are elevated in FMD indicating derangement of the TGFB pathway, and treatment with losartan or other angiotensin receptor blockers that modulate the pathway may be of benefit in the treatment of patients suffering from FMD.

National Institute of Health (NIH)
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