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Objective: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and 6 additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections ( P =0.005)., Conclusions: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.

Importance: Fibromuscular dysplasia (FMD) is a nonatherosclerotic arterial disease that predominately affects women and is most commonly diagnosed in middle age. The natural history of FMD among patients diagnosed at an older age is not well understood., Objective: To examine the differences in clinical presentation, arterial bed involvement, vascular events, and need for vascular procedures between younger and older patients with FMD., Design, Setting, and Participants: Analysis of baseline data for patients enrolled in the US Registry for FMD as of December 15, 2016, at referral centers participating in the US Registry for FMD. Patients 18 years and older at the time of enrollment and those with only confirmed multifocal (string of beads type) FMD were included. Patients were categorized according to age at the time of diagnosis (≥65 years vs <65 years)., Main Outcomes and Measures: Prevalence of specific symptoms, vascular events, and prior vascular procedures at the time of enrollment in the registry., Results: A total of 1016 patients were included in the analysis, of whom, 170 (16.7%) were 65 years or older at the time of diagnosis. Older patients with FMD were more likely to be asymptomatic at the time of diagnosis (4.2% vs 1.4%; P = .02). Headache and pulsatile tinnitus, both common manifestations of FMD, were less common in older patients (40.5% vs 69.1%; P < .001 and 30% vs 44.6%; P < .001, respectively). Extracranial carotid arteries were more commonly involved in patients 65 years or older at time of diagnosis (87% vs 79.4%; P = .03). There was no difference in prevalence of renal artery involvement, number of arterial beds involved, or diagnosis of any aneurysm. Patients 65 years or older were less likely to have had a major vascular event (37.1% vs 46.1%; P = .03) and fewer had undergone a therapeutic vascular procedure (18.5% vs 33.1%; P < .001)., Conclusions and Relevance: In the US Registry for FMD, patients 65 years or older at the time of diagnosis of multifocal FMD were more likely to be asymptomatic, had lower prevalence of major vascular events, and had undergone fewer therapeutic vascular procedures than younger patients. Patients with multifocal FMD diagnosed at an older age may have a more benign phenotype and fewer symptoms.

Background: Fibromuscular dysplasia (FMD) is a noninflammatory arterial disease that predominantly affects women. The arterial manifestations may include beading, stenosis, aneurysm, dissection, or tortuosity., Objectives: This study compared the frequency, location, and outcomes of FMD patients with aneurysm and/or dissection to those of patients without., Methods: The U.S. Registry for FMD involves 12 clinical centers. This analysis included clinical history, diagnostic, and therapeutic procedure results for 921 FMD patients enrolled in the registry as of October 17, 2014., Results: Aneurysm occurred in 200 patients (21.7%) and dissection in 237 patients (25.7%); in total, 384 patients (41.7%) had an aneurysm and/or a dissection by the time of FMD diagnosis. The extracranial carotid, renal, and intracranial arteries were the most common sites of aneurysm; dissection most often occurred in the extracranial carotid, vertebral, renal, and coronary arteries. FMD patients with dissection were younger at presentation (48.4 vs. 53.5 years of age, respectively; p < 0.0001) and experienced more neurological symptoms and other end-organ ischemic events than those without dissection. One-third of aneurysm patients (63 of 200) underwent therapeutic intervention for aneurysm repair., Conclusions: Patients with FMD have a high prevalence of aneurysm and/or dissection prior to or at the time of FMD diagnosis. Patients with dissection were more likely to experience ischemic events, and a significant number of patients with dissection or aneurysm underwent therapeutic procedures for these vascular events. Because of the high prevalence and associated morbidity in patients with FMD who have an aneurysm and/or dissection, it is recommended that every patient with FMD undergo one-time cross-sectional imaging from head to pelvis with computed tomographic angiography or magnetic resonance angiography., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Patients with fibromuscular dysplasia (FMD) may have clinical features consistent with Mendelian vascular connective tissue disorders. The yield of genetic testing for these disorders among patients with FMD has not been determined. A total of 216 consecutive patients with FMD were identified. Clinical characteristics were collected and genetic test results reviewed for abnormalities in the following genes: transforming growth factor-β receptor 1 and 2 (TGFβR1 and TGFβR2), collagen 3A1, fibrillin-1, smooth muscle α-actin 2, and SMAD3. A total of 63 patients (63/216; 29.2%) were referred for genetic counseling with testing performed in 35 (35/63; 55.6%). The percentage of patients with a history of arterial or aortic dissection, history of aortic aneurysm, systemic features of a connective tissue disorder, and a family history of sudden death was significantly larger in the group that underwent genetic testing (62.9% vs 18.2%, p < 0.001; 8.6% vs 1.7%, p = 0.02; 51.4% vs 17.1%, p < 0.001; and 42.9% vs 22.7%, p = 0.04, respectively). Two patients were found to have distinct variants in the TGFβR1 gene (c.611 C>T, p.Thr204lle and c.1285 T>C, p.Tyr429His). The yield of genetic testing for vascular connective tissue disorders was low in a high-risk subset of FMD patients. However, two patients with a similar phenotype had novel and distinct variants in the TGFβR1 gene, a finding which merits further investigation.

Patient advocacy groups provide physicians with a unique perspective of what is important to patients and a platform to allow patients to participate in improving care. Over the past few decades, there has been a wider recognition of peripheral vascular disease as a unique set of disease processes that affect a larger population of patients than initially appreciated. Finally, crowdsourcing, where patients can submit their own data and samples, is a unique way to increase patient recruitment and participation, and is an underutilized method for patient recruitment and participation. Most patients presenting with AAD aneurysm do so at sizes below prophylactic guidelines for aneurysm repair, with ascending diameters < 5.0 cm in 40% of Type A patients, and descending diameters < 5.5 cm in 81.6% of Type B patients. [Extracted from the article]