Classical Ehlers-Danlos syndrome (cEDS) is a rare connective tissue disorder primarily characterized by hyperextensible skin, defective wound healing, abnormal scars, easy bruising, and generalized joint hypermobility; arterial dissections are rarely observed. Mutations in COL5A1 and COL5A2 encoding type V collagen account for more than 90% of the patients so far characterized. In addition, cEDS phenotype was reported in a small number of patients carrying the c.934C>T mutation in COL1A1 that results in an uncommon substitution of a non-glycine residue in one Gly-Xaa-Yaa repeat of the pro-α1(I)-chain p.(Arg312Cys), which leads to disturbed collagen fibrillogenesis due to delayed removal of the type I procollagen N-propeptide. This specific mutation has been associated with propensity to arterial rupture in early adulthood; indeed, in literature the individuals harboring this mutation are also referred to as "(classic) vascular-like" EDS patients. Herein, we describe a three-generation cEDS family with six adults carrying the p.(Arg312Cys) substitution, which show a variable and prevalent cutaneous involvement without any major vascular event. These data, together with those available in literature, suggest that vascular events are not a diagnostic handle to differentiate patients with the p.(Arg312Cys) COL1A1 mutation from those with COL5A1 and COL5A2 defects, and highlight that during the diagnostic process the presence of at least the p.(Arg312Cys) substitution in COL1A1 should be investigated in cEDS patients without type V collagen mutations. Nevertheless, for these patients, as well as for those affected with cEDS, a periodical vascular surveillance should be carried out together with cardiovascular risk factors monitoring. © 2016 Wiley Periodicals, Inc.

Previous studies have reported an increased prevalence of osteoporosis in Ehlers–Danlos syndrome (EDS), but these were limited by a small number of patients and lack of information on fragility fractures. In this crosssectional study, we evaluated the prevalence of radiological vertebral fractures (by quantitative morphometry) and bone mineral density (BMD, at lumbar spine, total hip and femoral neck by dual-energy X-ray absorptiometry) in 52 consecutive patientswith EDS (10 males, 42 females; median age 41 years, range: 21–71; 12with EDS classic type, 37 with EDS hypermobility type, 1 with classic vascular-like EDS, and 2 without specific classification) and 197 control subjects (163 females and 34 males; median age 49 years, range: 26–83) attending an outpatient bone clinic. EDS patients were also evaluated for back pain by numeric pain rating scale (NRS- 11).Vertebral fractures were significantly more prevalent in EDS as compared to the control subjects (38.5% vs. 5.1%; p b 0.001) without significant differences in BMD at either skeletal sites. In EDS patients, the prevalence of vertebral fractures was not significantly (p = 0.72) different between classic and hypermobility types. BMD was not significantly different between fractured and non-fractured EDS patients either at lumbar spine (p = 0.14), total hip (p=0.08), or femoral neck (p=0.21). Severe back pain(≥7 NRS)was more frequent in EDS patients with vertebral fractures as compared to thosewithout fractures (60% vs. 28%; p=0.04). Inconclusion, this is the first study showing high prevalence of vertebral fractures in a relatively large population of EDS patients. Vertebral fractures were associated with more severe back pain suggesting a potential involvement of skeletal fragility in determining poor quality of life. The lack of correlation between vertebral fractures and BMD is consistent with the hypothesis that bone quality may be impaired in EDS.