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

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.

Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia

“…Our WES data are consistent with previous data using direct sequencing reported for an overlapping list of these genes in 47 FMD patients [11]. Interestingly, this study described deep clinical exploration that showed that FMD patients presented in high proportion connective tissue features such as early-onset degenerative spine disease, dural ectasia and mild connective tissue dysplasia [11].…”

“…collagens, fibrillins) in the media and an alteration of TGFb signalling are highly suspected. In support of this, a recent study reported features of connective tissue disease and the elevation of transforming growth factor-beta (TGFb)-1 and TGFb-2 in plasma from FMD patients [11].…”

“…Interestingly, this study described deep clinical exploration that showed that FMD patients presented in high proportion connective tissue features such as early-onset degenerative spine disease, dural ectasia and mild connective tissue dysplasia [11]. In addition, this study reported elevated circulating TGF-b1 and TGF-b2 and in media secreted by dermal fibroblasts from FMD patients, which suggests that the expression alteration of this pathway may be at the origin of these clinical features in FMD patients, similarly to clinical characteristics of patients with Loeys-Dietz and Marfan syndromes [11]. Therefore, causative genes for FMD could be yet to be identified modifiers of the TGF-b signalling and connective tissue components regulators.…”

“…FMD shares many clinical, histological and potentially some biological features with several vascular and connective tissue diseases [11]. Mutated molecules of collagen and fibrillin cause stenosis and dissection, as does impaired TGFb signalling in Elhers-Danlos and Loeys-Dietz syndrome, for instance.…”

“…Mutated molecules of collagen and fibrillin cause stenosis and dissection, as does impaired TGFb signalling in Elhers-Danlos and Loeys-Dietz syndrome, for instance. We specifically analysed the sequencing data for 16 candidate genes that were previously and firmly identified as causative in genetically mediated vascular and connective tissue disorders as reported previously [11,27]. In the intrafamilies analyses (Fig.…”