*3.3. Overlap with Genetic Syndromes*

Vascular abnormalities associated with FMD include arterial stenosis, tortuosity, aneurysms and dissections in one or more arterial beds [1]. Patients with rare inherited arteriopathies and connective tissue diseases (CTD) may harbour similar lesions. Furthermore, a proportion of patients with FMD harbour non-vascular features associated with CTD, suggesting an overlap between these entities and a possible role of the corresponding genes in non-syndromic FMD. In a cohort of 47 multifocal FMD patients, without family history of CTD, 95.7% of subjects presented radiological features, such as cerebral aneurysm (12.8%), early onset degenerative spine disease (95.7%), increased incidence of Arnold-Chiari I malformation (6.4%) and dural ectasia (42.6%) [36]. However, genetic screening failed to identify mutations in genes involved in hereditary CTD (*COL3A1*, *FBN1*, *PLOD1*, *TGFβR1*, *TGFβR2*, *TGFβ2*, *SMAD3*, *ACTA2*, and *COL5A1*) [36]. The most frequent clinical CTD features in a cohort of 139 female patients with FMD from the US registry were early onset (before age 50) osteoarthritis (15.6%), palatal abnormalities (56.1%), moderately severe myopia (29.1%), pectus excavatum or carinatum (7.2%), and dental crowding (29.7%) [37]. However, the prevalence of classical CTD features was estimated at 18.7%, similar to the general female population [37]. Finally, no mutation in *TGFβR2*, *COL3A1*, *FBN1*, *ACTA2*, or *SMAD3* gene was detected in a series of 35 FMD patients, again from the US registry. In this cohort, two distinct variants were identified in transforming growth factor beta receptor 1 (*TGFβR1*) gene in two unrelated patients. Both variants induced an amino acid substitution in a highly conserved region of *TGFβR1*, however their role is unknown [38]. Still, these findings may be relevant in view of the identification of increased plasma transforming growth factor beta-1 (TGF-β1) and transforming growth factor beta-2 (TGF-β2) secretion in dermal fibroblast lines from patients with FMD compared to age and gender-matched controls [36]. Overall, while FMD and CTD share some similarities, arguments in favour of a common genetic basis are scarce.
