Other FMD Research Findings

 

October, 2016, World Stroke Conference, India

Doctors Richard Hughes and Maria Nagel from the Department of Neurology,University of Colorado School of Medicine preseted an abstract titled  "Herpes Simplax Virus (HSV) Infection in the Acute Presentation of Fibromuscular Dysplasia (FMD)" at the 2016 World Stroke Conference in Hyderabad India. To view the abstract, click here


 

Increased Prevalence of Preeclampsia among Women Undergoing Procedural Intervention for Renal Artery Fibromuscular Dysplasia.

C.J. Vance, R.N. Taylor, T.E. Craven, .S. Edwards, M.A. Corriere.
Annals of Vascular Surgery

Abstract - Background: Renal artery fibromuscular dysplasia (RA-FMD) has a higher prevalence among women and a presumed hormonal etiology. Although preeclampsia has a clinical presentation similar to symptomatic RA-FMD and occurs exclusively in women, associations between these 2 diseases have not been characterized. To explore epidemiologic associations between RA-FMD and preeclampsia, we administered a validated screening instrument for preeclampsia to a cohort of women with a history of pregnancy who had previously been treated with procedural intervention for symptomatic RA stenosis. Results: A total of 144 women were identified who met the study inclusion criteria, including 94 with atherosclerotic renal artery stenosis and 50 with renal artery FMD. Sixty nine patients were contacted, 59 consented to participate, and 52 had a history of pregnancy (and therefore were at risk for preeclampsia). Participants completed the survey instrument at a mean of 7.1 ± 3.1 versus 6.9 ± 3.6 years after renal artery procedural intervention, respectively. Survey responses indicated a history of preeclampsia in 19/52 (36.5%) of participants overall, including 14/27 (51.9%) with renal artery FMD versus 5/20 (20.0%) with renal artery atherosclerosis (P=0.02). Preeclampsia remained associated with FMD in a multivariable model adjusting for smoking status, age at time of surgery, and estimated glomerular filtration rate (OR 9.51; 95% CI [1.49-60.6]; P=0.017); age at time of surgery (OR 2.78; 95% CI [1.04-7.42]; P=0.041) and estimated glomerular filtration rate (OR 3.31; 95% CI [1.29-8.52]; P=0.013) were also associated with FMD in the multivariable model. Conclusions: Women with a history of procedural intervention for symptomatic renal artery stenosis have an overall prevalence of preeclampsia which greatly exceeds that expected in the general population, and our results suggest that preeclampsia is specifically associated with renal artery FMD. Further investigation is needed to characterize the mechanistic relationships between FMD and prseeclampsia and may have potential to decrease related cardiovascular morbidity and mortality.


 

A "pivot" Model to set up Large Scale Rare Diseases Information Systems: Application to Fibromuscular Dysplasia Registry.

L. Toubiana, A. Ugon, A. Giavarini, J. Riquier, J. Charlet, X. Jeunemaitre, P.F. Plouin, M.C. Jaulent.
Stud Health Technol Inform. 2015;210:887-91.

Abstract - The SIR-FMD project is a partnership between the Department of Genetics and Reference Centre for Rare Vascular Diseases at the Georges Pompidou European Hospital in Paris and the Medical Informatics and Knowledge Engineering Laboratory of Inserm. Its aim is to use an ontological approach to implement an information system for the French Fibromuscular Dysplasia Registry. The existing data was dispersed in numerous databases, which had been created independently. These databases have different structures and contain data of diverse quality. The project aims to provide generic solutions for the management of the communication of medical data. The secondary objective is to demonstrate the applicability of these generic solutions in the field of rare diseases (RD) in an operational context. The construction of the French FMD registry was a multistep process. A secure platform has been available since the beginning of November 2013. The medical records of 471 patients from the initial dataset provided by the HEGP-Paris, France have been included, and are accessible from a secure user account. Users are organized into a collaborative group, and can access patient groups. Each electronic patient record contains more than 2,200 items. The problem of semantic interoperability has become one of the major challenges for the development of applications requiring the sharing and reuse of data. The information system component of the SIR-FMD project has a direct impact on the standardisation of coding of rare diseases and thereby contributes to the development of e-Health.


 

Exome Sequencing in Seven Families and Gene-Based Association Studies Support Genetic Heterogeneity and Suggest Possible Candidates for Fibromuscular Dysplasia.

S. Kiando, P.F. Plouin, M.C. Barlassina, D. Cusi, P. Galan, M. Lathrop, X. Jeunemaître, N. Bouatia-Naji  Journal of Hypertension. June 2015; 33 Suppl 1: e79. doi: 10. 1097/01.hjh.0000467566.26208.1a 

Abstract- Objective: Fibromuscular dysplasia (FMD) is a group of nonatherosclerotic and noninflammatory vascular disease leading to stenosis, aneurysm and dissection of medium-sized arteries, mainly renal arteries and carotids. FMD occurs predominantly in females with a prevalence of ∼ 4/1000 for clinical forms that cause hypertension, renal ischemia or stroke. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation. Our study objective is to identify genetic variants involved in FMD aetiology. Design and Method: We performed whole exome sequencing (WES) in 16 FMD cases from 7 families (5 sibpairs and 2 sibtrios). Coding variants in 3,971 genes confidently called (read depth>20X) were prioritized on their frequency (allele frequency<0.01) and in silico predicted functionality. Results: No gene harbored variants that were shared among all affected members of at least 3 out of 7 families. Rare coding variants from 16 known causative genes of vascular and connective tissue syndromes (e.g. FBN1, TGFB2 and COL3A1) were excluded as causative in these families. Genes with at least 4 rare coding variants identified in the 16 patients were followed-up using genotyping data by exome chip (Illumina HumanExome-12v1_A Beadchip) from 249 FMD unrelated cases and 689 controls. Gene-based association of rare variants using SKAT-O showed nominal significant (P<0.05) association with multifocal FMD (N=164) for OBSCN encoding a sarcomeric protein (P=0.003), DYNC2H1 encoding a cytoplasmic dynein (P=0.02) and RNF213 previously associated with Moyamoya disease (P=0.01). Conclusion: Our study reports data from the first WES investigation conducted for familial forms of FMD. It supports strong genetic heterogeneity for FMD and excludes the implication of several known vascular diseases causative genes in familial FMD etiology. We provide some evidence of association with multifocal FMD for OBSCN, DYNC2H1 and RNF213, though these findings need to be confirmed in independent cohorts. More powerful WES and association studies (e.g GWAS) will better decipher the genetic basis of FMD.


 

Flow-Mediated Dilatation (FMD) and Endothelium-Independent Dilitation (EID) in Patients with Multifocal Fibromuscular Dysplasia: A Cross-Sectional Study.

H. Khettab, A. Lorthior, R. Niarra, Y. Chambon, X. Jeunemaître, P.F. Plouin, S. Laurent, P. Boutouyrie, M. Azizi.                                                                                                                                                                                 Journal of Hypertension. June 2015; 33 Suppl 1:e82-3. doi: 10.1097/01.hjh.0000467574.64325.90. 

Abstract- Objective: Fibromuscular dysplasia (FD) is a rare idiopathic, segmental, non-atherosclerotic non-inflammatory vascular disease. We previously showed that FD is a general arterial disease with focal exacerbation of the trait. However, whether endothelial dysfunction may be involved in the pathophysiology of FD is unclear. Design and MethodIn a cross sectional study, we compared the endothelial function between 50 patients with multifocal FD of renal/carotid arteries confirmed by CT-angiography, 50 essential hypertensive (EH) patients matched for age, sex, ethnicity and BP and 50 healthy subjects (HS) matched for age, sex and ethnicity. Exclusion criteria were: tobacco consumption, hypercholesterolemia, diabetes, aspirin or statin treatment. Brachial artery (BA) FMD after release of hand ischemia and glyceryl trinitrate (GTN)-induced EID was measured using a high-resolution radiofrequency-based echotracking system blind to the diagnosis. Results: FD, EH and HS were well matched (52yrs, 85% women, 80% caucasian). SBP was higher in FD (125±15mmHg) and EH (121±12mmHg) than EH (113±10mmHg) despite antihypertensive treatments. BA external diameter was significantly lower in FD than in both HS and EH before, during and after hand ischemia and after GTN. BA intima media thickness (IMT), internal diameter did not differ between the 3 groups. FMD (%) or EID (%) did not significantly differ between the 3 groups. BA flow velocity did not significantly differ in any experimental condition.(Figure is included in full-text article.) ConclusionIn conclusion, despite showing similar acute vasodilatory responses to flow and GTN, FD patients differed from EH and HS in terms of arterial morphology with smaller BA diameter associated with similar IMT. This paradoxical remodeling may suggest a chronic defect in the endothelium-dependent pathways involved in arterial remodeling in FD patients.


 

Fibromuscular Dysplasia: An Update for the Headache Clinician.

S.C. O'Connor, N. Poria, H.L. Gornik.
Headache: The Journal of Head and Face Pain.  April 17, 2015.  Published online before print.

Abstract - Background: Fibromuscular dysplasia (FMD) is an uncommon vascular disease that presents with stenosis, aneurysm, dissection, beading, and tortuosity of medium-sized arteries. It primarily manifests in the renal and extracranial carotid and vertebral arteries, and is associated with major vascular events such as carotid artery dissection, renal artery dissection, ruptured aneurysm, transient ischemic attack, stroke, and myocardial infarction (due to coronary artery dissection). Discussion: There is a wide spectrum of disease severity among FMD patients. Symptoms of FMD are related to the vascular beds involved and the severity of arterial stenoses. Headache is an extremely common and important symptom reported by patients with FMD, although the precise mechanism of headache in this population is not yet known. Conclusion: This review summarizes the most recent literature regarding FMD, including epidemiology, clinical manifestations, imaging practices, and treatment. Special attention will be paid to the association of headaches and FMD. Correct diagnosis, optimal medical management, and appropriate referral for vascular intervention are vital elements of the treatment of patients with FMD. There is a great need for more clinical research regarding the epidemiology, pathophysiology, and optimal treatment of headache in the FMD patient population.



Fibromuscular Dysplasia: Renewed Awareness and New Insights Regarding an Orphan Disease.

E. Brinza, H.L. Gornik.  
Journal of the American College of Cardiology.  February 27, 2015.  Published online before print.

Published last month in JACC, this piece by Ellen Brinza and Heather Gornik chronicles new findings in the world of FMD research and offers future directions for researchers in the field.  For those recently diagnosed with FMD or anyone looking to learn about recent developments, this is a great article to get you up to speed.  You can find the full article here.



Carotid-Bulb Atypical Fibromuscular Dysplasia in Young Afro-Caribbean Patients with Stroke.

J. Joux, N. Chausson, S. Jeannin, M. Saint-Vil, M. Mejdoubi, J.L. Hennequin, L. Deschamps, D. Smadja, S. Olindo.
Stroke.  October 30, 2014.  Published online before print.

Abstract:  Background and Purpose—An atypical form of fibromuscular dysplasia located in the internal carotid-bulb (CaFMD) is thought to be uncommon and is poorly described as a cause of ischemic stroke in the young. This study aimed to obtain a better description of CaFMD in Afro-Caribbean population, who could be particularly affected by it.
MethodsThis study included consecutive patients <55 years consulting at Fort-de-France University Hospital Stroke Center (Martinique, FWI) found to have CaFMD as the only cause after a comprehensive work-up. CaFMD was diagnosed when computed tomographic angiography showed a bulbar spur without calcification.
ResultsTwenty-five patients with stroke and CaFMD were identified. Computed tomographic angiography showed 2 CaFMD patterns: a thin (n=15) or thick (n=10) spur. Three patients initial computed tomographic angiography images showed a mural thrombus overlying the CaFMD. CaFMD was surgically removed from 7 of 25 and 20 of 25 patients who received antiplatelet therapy; after mean follow-up of 25.3±19.5 months, their respective recurrence rates were 0% and 30%.
ConclusionsCaFMD could be a common condition in young Afro-Caribbeans with carotid-territory ischemic stroke. Recurrences were frequent under antiplatelet treatment, while surgical CaFMD removal seemed more effective.



Is fibromuscular dysplasia underdiagnosed? A comparison of the prevalence of FMD seen in CORAL trial participants versus a single institution population of renal donor candidates.

N.H. Hendricks, A.H. Matsumoto, J.F. Angle, A. Baheti, S.S. Sabri, A.W. Park, J.R. Stone, J.T. Patrie, L. Dworkin, C.J. Cooper, T.P. Murphy, D.E. Cutlip.
Vasc Med. October 2014, vol. 19. 5363-367

Abstract: Renal artery fibromuscular dysplasia (FMD) may be underdiagnosed. We evaluated the prevalence of FMD in CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) renal artery stent trial participants, in which FMD was an exclusion criterion for inclusion. We also evaluated the prevalence of FMD in a relatively healthy population of patients undergoing computed tomographic angiographic (CTA) screening for renal donor evaluation. All renal donor CTAs performed at our institution from January 2003 through November 2011 were retrospectively reviewed for the presence of FMD along with patient sex and age. These results were compared to angiographic core lab (ACL) findings for the CORAL trial. The CORAL ACL database contained 997 patients (mean age 69.3 years; 50% female). Fifty-eight (5.8%) CORAL trial patients (mean age 71.8 years; 75.9% female) demonstrated incidental FMD. The renal donor cohort included 220 patients (mean age 40.5 years; 64.5% female). Five (2.3%) demonstrated FMD (mean age 48.6 years; all female). The odds of FMD in the CORAL cohort were 2.65 times that seen in the renal donor cohort (95% CI: 1.12, 7.57). In conclusion, the 5.8% prevalence of renal artery FMD in the CORAL trial population, the presence of which was biased against, suggests underdiagnosis.



The S curve: A novel morphological finding in the internal carotid artery in patients with fibromuscular dysplasia.

S.S. Sethi, J.F. Lau, J. Godbold, S. Gustavson, J.W. Olin.
Vasc Med. October 2014, vol. 19. 5356-362

Abstract: Fibromuscular dysplasia (FMD) is a non-atherosclerotic vascular disease commonly affecting the renal and internal carotid arteries (ICAs). A previously unrecognized finding is a redundancy of the mid-distal ICA in FMD patients causing an ‘S’-shaped curve. Carotid artery duplex ultrasounds were reviewed in 116 FMD patients to determine S-curve prevalence. FMD patients with an S curve were matched to four control patients divided equally into two groups: (1) age and sex-matched and (2) age ≥70 and sex-matched. S curves were present in 37 (32%) FMD patients. Of these, nine (24%) had angiographic evidence of FMD in their ICA only, 13 (35%) had renal artery FMD only, and 15 (41%) had both ICA and renal FMD. Two patients in the age and sex-matched group had S curves (odds ratio 16.86, 95% CI 3.92–72.48; p<0.0001) while 12 (16.2%) patients in the age ≥70 and sex-matched group had S curves (odds ratio 2.42, 95% CI 1.16–5.03; p=0.016). In conclusion, the S curve is a novel morphological pattern of the mid-distal ICA. While the S curve may not be specific, its presence in individuals <70 years old should alert the clinician to the possibility that FMD is present.



Brachial Artery Fibromuscular Dysplasia: A Case Series

J. West, N. Hendricks, A. Matsumoto, A.M. Sharma.

Abstract: Background: Fibromuscular dysplasia (FMD) is a noninflammatory arteriopathy that has multiple different angiographic appearances. FMD can involve multiple vascular beds and typically involves renal arteries and cerebrovascular arteries. FMD of the brachial artery is a rare entity with only a handful of case reports in the literature. We present a case series of patients with brachial FMD.  Methods: We queried our database at University of Virginia from March 2008 to December 2013 to identify patients with brachial FMD and a retrospective chart review was performed.  Results: Of the 225 patients, 7 patients had brachial FMD: 6/7 were women. Brachial FMD was diagnosed with CT or invasive angiogram in six patients and one was diagnosed with duplex ultrasonography. Four were symptomatic: 3 presenting with embolic event and 1 with claudication. All symptomatic patients underwent angioplasty with some or complete relief of symptoms. Identification of 2/3 asymptomatic patients was by brachial bruit confirmed with imaging and 1 was incidentally diagnosed on imaging. Age ranged from 29 to 68 years, with delays between initial FMD diagnosis in other vessels and diagnosis of brachial FMD from 0 days to 9 years. Four of 7 patients had FMD in multiple arterial beds ranging from 2 to 6 different beds and all were multifocal in appearance. All of them had hypertension with 4 diagnosed with renal FMD. One patient had a cervical dissection and 1 had a radial pseudoaneurysm.  Conclusion: Brachial FMD is a rare, easily overlooked finding, but can be clinically important. A thorough examination including assessing for brachial bruits and obtaining blood pressure in both arms is extremely vital in this group of patients.

noninflammatory arteriopathy that has multiple different 
angiographic appearances. FMD can involve multiple 
vascular beds and typically involves renal arteries and 
cerebrovascular arteries. FMD of the brachial artery is a rare 
entity with only a handful of case reports in the literature. 
We present a case series of patients with brachial FMD.
Methods: We queried our database at University of 
Virginia from March 2008 to December 2013 to identify 
patients with brachial FMD and a retrospective chart 
review was performed.
Results: Of the 225 patients, 7 patients had brachial 
FMD: 6/7 were women. Brachial FMD was diagnosed 
with CT or invasive angiogram in six patients and one 
was diagnosed with duplex ultrasonography. Four were 
symptomatic: 3 presenting with embolic event and 1 
with claudication. All symptomatic patients underwent 
angioplasty with some or complete relief of symptoms. 
Identification of 2/3 asymptomatic patients was by brachial 
bruit confirmed with imaging and 1 was incidentally 
diagnosed on imaging. Age ranged from 29 to 68 years, with 
delays between initial FMD diagnosis in other vessels and 
diagnosis of brachial FMD from 0 days to 9 years. Four of 
7 patients had FMD in multiple arterial beds ranging from 
2 to 6 different beds and all were multifocal in appearance. 
All of them had hypertension with 4 diagnosed with renal 
FMD. One patient had a cervical dissection and 1 had a 
radial pseudoaneurysm.
Conclusion: Brachial FMD is a rare, easily overlooked 
finding, but can be clinically important. A thorough 
examination including assessing for brachial bruits and 
obtaining blood pressure in both arms is extremely vital in 

This abstract was presented at the Society of Vascular Medicine's 25th Annual Meeting.  You can read more articles from the meeting here.

noninflammatory arteriopathy that has multiple different 
angiographic appearances. FMD can involve multiple 
vascular beds and typically involves renal arteries and 
cerebrovascular arteries. FMD of the brachial artery is a rare 
entity with only a handful of case reports in the literature. 
We present a case series of patients with brachial FMD.
Methods: We queried our database at University of 
Virginia from March 2008 to December 2013 to identify 
patients with brachial FMD and a retrospective chart 
review was performed.
Results: Of the 225 patients, 7 patients had brachial 
FMD: 6/7 were women. Brachial FMD was diagnosed 
with CT or invasive angiogram in six patients and one 
was diagnosed with duplex ultrasonography. Four were 
symptomatic: 3 presenting with embolic event and 1 
with claudication. All symptomatic patients underwent 
angioplasty with some or complete relief of symptoms. 
Identification of 2/3 asymptomatic patients was by brachial 
bruit confirmed with imaging and 1 was incidentally 
diagnosed on imaging. Age ranged from 29 to 68 years, with 
delays between initial FMD diagnosis in other vessels and 
diagnosis of brachial FMD from 0 days to 9 years. Four of 
7 patients had FMD in multiple arterial beds ranging from 
2 to 6 different beds and all were multifocal in appearance. 
All of them had hypertension with 4 diagnosed with renal 
FMD. One patient had a cervical dissection and 1 had a 
radial pseudoaneurysm.
Conclusion: Brachial FMD is a rare, easily overlooked 
finding, but can be clinically important. A thorough 
examination including assessing for brachial bruits and 
obtaining blood pressure in both arms is extremely vital in 


Coronary Artery Manifestations of Fibromuscular Dysplasia

K.C. Michelis, J.W. Olin, D. Kadian-Dodov, V. d'Escamard, J.C. Kovacic.
J Am Coll Cardiol. 2014;64(10):1033-1046.

Abstract: Fibromuscular dysplasia (FMD) involving the coronary arteries is an uncommon but important condition that can present as acute coronary syndrome, left ventricular dysfunction, or potentially sudden cardiac death. Although the classic angiographic “string of beads” that may be observed in renal artery FMD does not occur in coronary arteries, potential manifestations include spontaneous coronary artery dissection, distal tapering or long, smooth narrowing that may represent dissection, intramural hematoma, spasm, or tortuosity. Importantly, FMD must be identified in at least one other noncoronary arterial territory to attribute any coronary findings to FMD. Although there is limited evidence to guide treatment, many lesions heal spontaneously; thus, a conservative approach is generally preferred. The etiology is poorly understood, but there are ongoing efforts to better characterize FMD and define its genetic and molecular basis. This report reviews the clinical course of FMD involving the coronary arteries and provides guidance for diagnosis and treatment strategies.



Altered TGF-β Expression in FMD - FASEB - April 2014

Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features.

S.K. Ganesh, R. Morisette, Z. Xu, F. Schoenhoff, B.F. Griswold, J. Yang, L. Tong, M. Yang, K. Hunker, L. Sloper, S. Kuo, R. Raza, D.M. Milewicz, C.A. Francomano, H.C. Dietz, J. Van Eyk, N.B. McDonnell.

Abstract:

Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor β (TGF-β) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-β1 (P=0.009), TGF-β2 (P=0.004) and additional inflammatory markers, and increased TGF-β1 (P=0.0009) and TGF-β2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-β signaling and offers TGF-β as a marker of FMD.



AHA Scientific Statement - Circulation - February 2014

Fibromuscular Dysplasia: State of the Science and Critical Unanswered Questions: A Scientific Statement From the American Heart Association.

J.W. Olin, H.L. Gornik, J.M. Bacharach, J. Biller, L.J. Fine, B.H. Gray, W.A. Gray, R. Gupta, N.M. Hamburg, B.T. Katzen, R.A. Lookstein, A.B. Lumsden, J.W. Newburger, T. Rundek, C.J. Sperati, J.C. Stanley.  Circulation 129.9 (2014): 1048-1078

This publication summarizes and encompasses all previous research on FMD, while also identifying important areas of future research, recommendations for imaging modalities and treatments, and suggests an updated classification system for the vascular disease.  The article reviews the history of FMD, genetic considerations, epidemiology, clinical manifestations and much more.  The authors suggest a reclassification of the disease into two distinct categories for ease of diagnosis and treatment: multifocal and focal FMD.  With this important publication, physicians and patients should be able to more easily recognize, classify, and treat this disease.  The paper is free and can be found on Circulation, Journal of the American Heart Association.


The abstracts below were presented at the American Society of Human Genetics Annual Meeting in October 2006.

A cohort of patients with generalized Fibromuscular Dysplasia and features of Ehlers-Danlos Syndrome: A new phenotype.

N.B. McDonnell, J. Yang, W. Chen1, B. Griswold, C.A. Francomano 1) National Institute on Aging, NIH, Baltimore, MD; 2) Harvey Inst Human Gen, Greater Baltimore Medical Center, Baltimore, MD.

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue. 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 TGFBR1 or TGFBR2. We have identified a group of patients without mutations in COL3A1, TGFBR1 or TGFBR2 who presented with arterial dissections and aneurysms as well as stenotic lesions with a diagnosis of fibromuscular dysplasia (FMD) by pathology or radiology. Varying features of Ehlers-Danlos syndrome, 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. There were no reports of uterine or bowel rupture, or pregnancy related death in personal or family histories. The facial features were not characteristic of VEDS or Loeys-Dietz syndrome. The first patient identified was a 44 year old woman who had a history of carotid dissection, ruptured cerebral aneurysms, FMD of renal arteries and iliac vessels, multiple atrophic scars, frequent joint dislocations, and stretchy and doughy skin. A cohort of thirty patients with this syndrome has been identified and detailed phenotype and family history information has been assembled. The etiology of fibromuscular dysplasia is thought to be heterogeneous, with genetic and environmental factors proposed as possible contributors. Our findings suggest that there is a previously unrecognized variant of EDS, distinct from the VEDS and Loeys-Dietz syndrome, with FMD as a major clinical feature in addition to the skin and joint abnormalities.


Genome wide association study for Fibromuscular Dysplasia (FMD)
J. Yang1, M. Nalls2, B. Traynor2, D. Hernandez2, N. Washecka2, B. Griswold1, L. Sloper1, A. Singleton2, N. B. McDonnell1 1) LCI, NIA/NIH, Baltimore, MD; 2) LNG,NIA/NIH, Bethesda, MD.

Fibromuscular dysplasia is a heterogeneous disorder characterized by angiopathy of the arteries, which predominantly affects women in mid-life, resulting in stenosis, dissection or aneurysm. It may involve renal arteries, carotid, vertebral, coronary and abdominal vessels. Autosomal dominant inheritance has been suggested, however no genes have been identified to date. On detailed clinical examination of a cohort of 69 patients seen at the National Institute on Aging, features of connective tissue dysplasia as exemplified by joint hypermobility, scoliosis, pectus deformity, pes planus and high myopia were frequently noted, suggesting a defect in the extracellular matrix pathways. In order to elucidate the genetic factors underlying this disorder, we performed genome wide association study in 46 sporadic cases and 540 controls utilizing the Illumina HumanCNV370-Duo BeadChip and HumanHap550 Beadchip. By permutation analysis, we have identified a number of marker SNPs with significant differences between cases and controls. The candidate genes include CDH12, EXOC2, PACRG, HECW1, ZAN, CSMD1, SRA and DIP2B with p scores <10-6. Although the disorders has been suggested to be dominant, we did homozygosity analyses for our samples, our results show chromosome 4, 5, 12 could include some specific overlapping homozygous runs in FMD patients.


Morphometric Analysis of the Posterior Fossa and Spinal Cord in patients with Hereditary Disorders of Connective Tissue
J. C. Quo1,2, L. Sloper1, R. Raza2, N. B. McDonnell1 1) Clinical Research Branch, NIA, NIH, Baltimore, MD; 2) Harbor Hospital Center, Baltimore, MD.

Patients with hereditary disorders of connective tissue (HDCT) have increased incidence of Chiari I malformation, however, abnormalities of the posterior fossa or the spinal cord has not been systematically evaluated to date. We retrospectively evaluated midline sagittal brain, midline sagittal lumbar spine, and axial lumbar magnetic resonance imaging (MRI) of 94 subjects with HDCT (70 Female, 24 Male, aged 12-71) and 209 age matched controls (138 Female, 71 Males). HDCT subjects included those with diagnoses of Ehlers-Danlos syndrome (EDS), Marfan syndrome, and Fibromuscular Dysplasia with connective tissue features (FMD). The MRI images were obtained on a 1.5 Tesla MRI machine (Philips Interna, USA) with system 11.1 software. The measurement that showed significant differences between the subjects and the controls included the basiocciput measurement (p=0.0115), foramen magnum distance (p=0.0101), opisthion to internal occipital protuberance (IOP) (p=0.0188), dorsa sella to IOP (p=0.0176), tonsillar herniation (p<0.0001), fourth ventricle height (p=0.0020), brainstem length to the craniocervical junction (p<0.0001), brainstem length to the inferior portion of the gracile tubercle (p=0.0016), tentorium slope (p=0.0109), tentorium slope to the twining line (p=0.0044), height of cerebellum (p<0.0001), conus medullaris level (p=0.0383), and filum terminale thickness (p<0.0001). Measurements that were not statistically significant included the basisphenoid length, ponto-medullary height, medullary height, and odontoid angle. The significant p value observed in 13 of the 17 measurements suggests that there are consistent morphometric differences that are seen in HDCT patients that can contribute to increased incidence of clinical abnormalities such as Chiari I malformation, tethered cord syndrome and related complaints.


Sex Hormone Abnormalities in patients with Fibromuscular Dysplasia with Connective Tissue Features
B. F. Griswold, L. Sloper, S. Basaria, J. M. Egan, N. B. McDonnell National Institute on Aging Baltimore, Maryland.

We have identified a group of patients (n=28) who presented with arterial dissections and aneurysms as well as stenotic lesions with a diagnosis of fibromuscular dysplasia (FMD). Varying features of Ehlers-Danlos syndrome, 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 in this group of patients, and family history data suggested autosomal dominant inheritance with reduced penetrance. There was a female preponderance, 24 women and 4 men, consistent with prior observations that FMD affects women predominantly, leading to the hypothesis that sex hormones played a role in the penetrance of the disorder. As part of a longitudinal protocol studying the natural history of this disorder, laboratory analysis of sex hormone levels was completed. Of the 24 female patients aged 33-62, 15 were post-menopausal. Of the women subjects, 8/24 (0.33) had high levels of Sex Hormone Binding Globulin (SHBG) which included four post menopausal patients. Free testosterone was low in 36 percent; of women patients, and 4/24 (0.17) had low bioavailable levels of testosterone. Of the 8 patients found to have high levels of SHBG, five also had corresponding low free testosterone. None of the patients had liver function abnormalities or current birth control pill use which are known to increase SHBG. None of the premenopausal patients had low FSH or LH along with low estrogen which would suggest pituitary failure. By contrast, the four male patients had normal levels of testosterone and SHBG, however the sample size was too small to draw conclusions. Elevated SHBG and low testosterone in women with FMD may be a clue to pathways involved in the etiology of this disorder.

Fibromuscular Dysplasia: Renewed Awareness and New Insights Regarding an Orphan Disease

- See more at: http://www.acc.org/latest-in-cardiology/articles/2015/02/27/08/54/fibromuscular-dysplasia-renewed-awareness-and-new-insights?w_nav=LC#sthash.Qp2QBWo9.dpuf

Fibromuscular Dysplasia: Renewed Awareness and New Insights Regarding an Orphan Disease

- See more at: http://www.acc.org/latest-in-cardiology/articles/2015/02/27/08/54/fibromuscular-dysplasia-renewed-awareness-and-new-insights?w_nav=LC#sthash.Qp2QBWo9.dpuf