vEDS Patients Research Articles

Is Exon Skipping a Viable Therapeutic Approach for Vascular Ehlers-Danlos Syndrome with Mutations in COL3A1 Exon 10 or 15?

Vascular Ehlers-Danlos syndrome or Ehlers-Danlos syndrome type IV (vEDS) is a connective tissue disorder characterised by skin hyperextensibility, joint hypermobility and fatal vascular rupture caused by COL3A1 mutations that affect collagen III expression, homo-trimer assembly and secretion. Along with collagens I, II, V and XI, collagen III plays an important role in the extracellular matrix, particularly in the inner organs. To date, only symptomatic treatment for vEDS patients is available. Fibroblasts derived from vEDS patients carrying dominant negative and/or haploinsufficiency mutations in COL3A1 deposit reduced collagen III in the extracellular matrix. This study explored the potential of an antisense oligonucleotide (ASO)-mediated splice modulating strategy to bypass disease-causing COL3A1 mutations reported in the in-frame exons 10 and 15. Antisense oligonucleotides designed to redirect COL3A1 pre-mRNA processing and excise exons 10 or 15 were transfected into dermal fibroblasts derived from vEDS patients and a healthy control subject. Efficient exon 10 or 15 excision from the mature COL3A1 mRNA was achieved and intracellular collagen III expression was increased after treatment with ASOs; however, collagen III deposition into the extracellular matrix was reduced in patient cells. The region encoded by exon 10 includes a glycosylation site, and exon 15 encodes hydroxyproline and hydroxylysine-containing triplet repeats, predicted to be crucial for collagen III assembly. These results emphasize the importance of post-translational modification for collagen III homo-trimer assembly. In conclusion, while efficient skipping of target COL3A1 exons was achieved, the induced collagen III isoforms generated showed defects in extracellular matrix formation. While therapeutic ASO-mediated exon skipping is not indicated for the patients in this study, the observations are restricted to exons 10 and 15 and may not be applicable to other collagen III in-frame exons.

Generation of two iPSC lines from vascular Ehlers-Danlos Syndrome (vEDS) patients carrying a missense mutation in COL3A1 gene

Vascular Ehlers-Danlos Syndrome (vEDS) is an inherited connective tissue disorder caused by COL3A1 gene, mutations that encodes type III collagen, a crucial component of blood vessels. vEDS can be life-threatening as these patients can have severe internal bleeding due to arterial rupture. Here, we generated induced pluripotent stem cell (iPSC) lines from two vEDS patients carrying a missense mutation in the COL3A1 (c.226A > G, p.Asn76Asp) gene. These lines exhibited typical iPSC characteristics including morphology, expression of pluripotency markers, and could differentiate to all three germ layer. These iPSC lines can serve as valuable tools for elucidating the pathophysiology underlying vEDS.

Deciphering disease signatures and molecular targets in vascular Ehlers-Danlos syndrome through transcriptome and miRNome sequencing of dermal fibroblasts

Vascular Ehlers-Danlos syndrome (vEDS) is a severe connective tissue disorder caused by dominant mutations in the COL3A1 gene encoding type III collagen (COLLIII). COLLIII is primarily found in blood vessels and hollow organs, and its deficiency leads to soft connective tissues fragility, resulting in life-threatening arterial and organ ruptures. There are no current targeted therapies available. Although the disease usually results from COLLIII misfolding due to triple helix structure disruption, the underlying pathomechanisms are largely unknown. To address this knowledge gap, we performed a comprehensive transcriptome analysis using RNA- and miRNA-seq on a large cohort of dermal fibroblasts from vEDS patients and healthy donors. Our investigation revealed an intricate interplay between proteostasis abnormalities, inefficient endoplasmic reticulum stress response, and compromised autophagy, which may significantly impact the molecular pathology. We also present the first detailed miRNAs expression profile in patient cells, demonstrating that several aberrantly expressed miRNAs can disrupt critical cellular functions involved in vEDS pathophysiology, such as autophagy, proteostasis, and mTOR signaling. Target prediction and regulatory networks analyses suggested potential interactions among miRNAs, lncRNAs, and candidate target genes linked to extracellular matrix organization and autophagy-lysosome pathway. Our results highlight the importance of understanding the functional role of ncRNAs in vEDS pathogenesis, shedding light on possible miRNAs and lncRNAs signatures and their functional implications for dysregulated pathways related to disease. Deciphering this complex molecular network of RNA interactions may yield additional evidence for potential disease biomolecules and targets, assisting in the design of effective patient treatment strategies.

Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics.

Vascular Ehlers-Danlos Syndrome (vEDS) is a rare autosomal dominant disease caused by mutations in the COL3A1 gene, which renders patients susceptible to aneurysm and arterial dissection and rupture. To determine the role of COL3A1 variants in the biochemical and biophysical properties of human arterial ECM, we developed a method for synthesizing ECM directly from vEDS donor fibroblasts. We found that the protein content of the ECM generated from vEDS donor fibroblasts differed significantly from ECM from healthy donors, including upregulation of collagen subtypes and other proteins related to ECM structural integrity. We further found that ECM generated from a donor with a glycine substitution mutation was characterized by increased glycosaminoglycan content and unique viscoelastic mechanical properties, including increased time constant for stress relaxation, resulting in a decrease in migratory speed of human aortic endothelial cells when seeded on the ECM. Collectively, these results demonstrate that vEDS patient-derived fibroblasts harboring COL3A1 mutations synthesize ECM that differs in composition, structure, and mechanical properties from healthy donors. These results further suggest that ECM mechanical properties could serve as a prognostic indicator for patients with vEDS, and the insights provided by the approach demonstrate the broader utility of cell-derived ECM in disease modeling. STATEMENT OF SIGNIFICANCE: The role of collagen III ECM mechanics remains unclear, despite reported roles in diseases including fibrosis and cancer. Here, we generate fibrous, collagen-rich ECM from primary donor cells from patients with vascular Ehlers-Danlos syndrome (vEDS), a disease caused by mutations in the gene that encodes collagen III. We observe that ECM grown from vEDS patients is characterized by unique mechanical signatures, including altered viscoelastic properties. By quantifying the structural, biochemical, and mechanical properties of patient-derived ECM, we identify potential drug targets for vEDS, while defining a role for collagen III in ECM mechanics more broadly. Furthermore, the structure/function relationships of collagen III in ECM assembly and mechanics will inform the design of substrates for tissue engineering and regenerative medicine.

Postmortem Identification of Vascular Ehlers-Danlos Syndrome in a Lung Transplant Recipient.

Postmortem Identification of Vascular Ehlers-Danlos Syndrome in a Lung Transplant Recipient.

Oral Health-Related Quality of Life in Different Subtypes of Ehlers-Danlos Syndrome.

This study assessed differences in the oral health-related quality of life (OHRQoL) between subtypes of Ehlers-Danlos syndrome (EDS). For statistical analysis, participants were divided according to their subtype: classical EDS (cEDS), hypermobile EDS (hEDS), and vascular EDS (vEDS). All other subtypes were descriptively analyzed. Free-text questions and the German short form of the Oral Health Impact Profile (OHIP-14) were used. Finally, 295 questionnaires were included, representing 10 different EDS subtypes. The mean OHIP score of all participants was 19.6 points (standard derivation (SD) ± 12.3). The most predominant subtypes showed similar reduced OHRQoL, with 18.0 (cEDS, ±12.9), 19.5 (hEDS, ±12.0), and 15.2 (vEDS, ±11.6) OHIP points. For all other subtypes, the OHIP values varied. Participants waited an average of 21.8 years (±12.8) for their diagnosis. However, within the predominant subtypes, vEDS patients waited a noticeably shorter period of 13.3 years (±13.0; p = 0.004) compared to participants with hEDS. Additionally, this study showed no difference in OHRQoL for the predominant subtypes regardless of whether a participant was a self-help group member (18.8, ±12.0) or not (19.4, ±12.1; p = 0.327).

Celiprolol to prevent arterial events in patients with vascular Ehlers-Danlos and neither symptomatic nor silent arterial event. A retrospective cohort study from the French national reference center

Abstract Background Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder, leading to mainly arterial complications, caused by COL3A1 pathogenic variations. Ong et al. (Lancet 2010) showed that the introduction of celiprolol significantly reduced arterial events in a predominantly symptomatic population on arterial level. We reported the benefit of full dose of Celiprolol in longitudinal study to prevent arterial events in Frank et al. (JACC 2019). To our knowledge, there is no data regarding the benefit of celiprolol in patients without any arterial event. Purpose The aim of this study was to assess the occurrence of arterial events during follow-up in vEDS patients without arterial event. Methods All patients – probands and relatives – with a pathogenic variation in COL3A1 diagnosed at the Referral Centre for Rare Vascular Diseases since 2001 and at least one arterial tree assessment were included. We then focused on vEDS patients without any arterial event. We retrospectively analyzed the duration of follow-up, the occurrence of arterial events during follow-up, and the introduction and dose of celiprolol, especially at the time of occurrence of an arterial event. Results Among the 230 patients included, 144 (63%) had at least one symptomatic arterial event, 44 (19%) had only silent arterial event and 67 (29%) had no arterial event at the first arterial tree assessment event. Patients with no arterial event were significantly younger at this visit compared with the two other groups with a median age of 23 vs. 38 and 39 years (silent and symptomatic) (p<0.05). Patients with no arterial event were more frequently relatives (73%) than probands (27%) (p<10–3). Celiprolol was introduced in 48 (72%) of the 67 patients with no arterial event after positive genetic diagnosis disclosure or during one of the outpatient visit. During follow-up, 22 patients had a first arterial event at a median age of 29 years: 16 (33%) were receiving celiprolol and 6 (32%) were not. But the median follow-up duration was 4 years for the 48 treated patients vs. 2 years for the 19 untreated patients (p=0.03). Conclusions Genetic testing of the relatives of probands with vEDS remains of utmost importance as one quarter presented with symptomatic arterial event and one fifth had silent arterial event at initial arterial tree assessment. For patients with no arterial event, those without celiprolol have a similar incidence of arterial events than those with celiprolol, however their follow-up duration was twice shorter suggesting a higher incidence rate or arterial event in the absence of celiprolol. Funding Acknowledgement Type of funding sources: None.

Assessment of arterial damage in vascular Ehlers-Danlos syndrome: a retrospective multicentric cohort

Abstract Background Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder due to pathogenic variants in the COL3A1 gene, leading to medium-size artery (MSA) dissection, aneurysm, and rupture with a poor prognosis. Conversely, aortic lesions are rarer and less investigated. Purpose To describe the association between the distribution of MSA and aortic lesions and the type of COL3A1 variants in a multicentric cohort of vEDS patients. Methods Analysis of the 330 vEDS adult patients from the French RaDiCO SEDVASC registry. At the time of the study, 87% were alive, 60.3% were index cases and 60.0% females. Median age at molecular diagnosis was 36 years (IQR 24.3–46.8). COL3A1 variants were identified using NGS and/or Sanger sequencing and classified according to their functional consequences: 80.6% dominant-negative (DN) and 19.4% leading to haplo-insufficiency (HI). Computed tomography angiography (CTA) was systematically performed during the initial work-up of patients. Carotid mechanics was also assessed by echotracking in a subgroup of 133 patients. Results Arterial lesion history was reported in 82.4% of the patients (N=272), with 227/272 patients (83.5%) having MSA lesions alone, 9 (3.3%) aortic lesions alone and 36 (13.2%) both. DN variant was associated with higher prevalence of arterial lesions than HI variant (P 0.044), especially on supra-aortic trunks and renal arteries (P 0.018 and P 0.0003 respectively). Importantly, the higher prevalence of aortic lesions observed in HI patients with arterial lesions versus DN patients (P 0.027) was not significantly different when adjusted for age (P 0.559). Carotid Young's modulus was lower in DN than HI patients (P 0.014), in association with the higher incidence of MSA lesions in this genotype group. Conclusion The prevalence of aortic lesions is not influenced by the COL3A1 genotype when adjusted for age. vEDS patients with DN variants have a higher frequency of MSA lesions especially in supra-aortic trunks which is associated with a lower carotid stiffness, suggesting a need for an optimal care for this subgroup of patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): French National Research Agency under the specific programme “Investments for the Future”, cohort grant-agreement ANR-l0-COHO-03-01

Surveillance and monitoring in vascular Ehlers-Danlos syndrome in European Reference Network For Rare Vascular Diseases (VASCERN)

Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic disorder clinically characterized by vascular, intestinal and uterine fragility and caused by heterozygous pathogenic variants in the COL3A1 gene. Management of patients with vEDS is difficult due to the unpredictability of the events and clear recommendations on the care of adults and children with vEDS are lacking. Therefore, we aimed to collect data on the current strategy of surveillance and monitoring of vEDS patients by expert centers in continental Europe and Great Britain, as a first step towards a consensus statement. A survey on the clinical management of vEDS was sent to all members of the Medium Sized Artery (MSA) Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) and other expert centers. All experts endorse the importance of monitoring patients with vEDS. Despite the absence of evidence based guidelines monitoring is considered in almost all countries, but screening intervals and modalities used for monitoring may differ among centers. There is a need for more prospective multicenter studies to define proper guidelines.

Early and Late Outcomes of Cardiovascular Surgery in Patients With Ehlers-Danlos Syndrome.

Cardiovascular surgical outcomes reports are few for vascular type IV of Ehlers- Danlos Syndrome (vEDS) compared to non-vascular types I-III (nEDS). To define cardiovascular surgical outcomes among adult patients (≥18 years) with EDS types, a review of our institution's in-house STS Adult Cardiac Surgery Database-compliant software and electronic medical records from Mayo Clinic (1993-2019) was performed. Outcomes were compared for vEDS patients and nEDS patients. Demographics, baseline characteristics, operative, in-hospital complications and follow-up vital status were analyzed. Over the study time frame, 48 EDS patients underwent surgery (mean age 52.6 ± 14.6 years; 48% females). Of these, 17 patients had vEDS and 31 patients had nEDS. Six patients (12.5%) underwent prior sternotomy. Urgent or emergent surgery was performed in 10 patients (20.8%). Aortic (vEDS 76.5% vs. nEDS 16.1%) and mitral procedures (vEDS 11.8% vs. nEDS 48.4%) were the two most common cardiovascular surgeries performed (p < .01 and p = .007, respectively). Cardiopulmonary bypass time (CPB) (165 ± 18 vs. 90 ± 13 min; p = .015) and aortic cross clamp times (140 ± 14 vs. 62 ± 10 min; p < .001) were longer for vEDS patients. There was 1 (2.1%) early and 7 (14.6%) late deaths; 6 among vEDS and 2 among nEDS patients. Survival at 5 (80% vs. 93%), 10 (45% vs. 84%) and 15 years (45% vs. 84%) was lower in patients with vEDS (p = .015 for each comparison). Cardiovascular surgeries are significantly more complex with longer bypass and cross clamp times for type IV vEDS compared to nEDS patients. Reduced overall survival underscores the complexity and fragility of vEDS patients.

Vascular Ehlers-Danlos Syndrome: Pathological Variants, Recent Discoveries, and Theoretical Approaches.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant genetic disorder. It is the most fatal among all types of EDS. In addition to typical EDS characteristics, vEDS patients are at risk of blood vessel rupture due to possession of pathogenic variants of the COL3A1 gene, which encodes type III collagen. Type III collagen is a major component of humans' vascular walls. The management of this disease is possible; however, there is no cure as of present. Recently, discoveries with potential impact on the management of vEDS have been elucidated. Mice with vEDS traits treated with a beta-blocker celiprolol showed significant improvements in their thoracic aorta biomechanical strength. Moreover, it has been demonstrated that the specifically designed small interference RNAs (siRNA) can effectively silence the pathogenic variant allele. To enhance the normal allele expression, an intracellularly expressed lysyl oxidase is shown to regulate the transcription rate of the COL3A1 promoter. Similarly, an embryonic homeobox transcription factor Nanog upregulates the wild-type COL3A1 expression through activation of the transforming growth factor-beta pathway, which increases type III collagen synthesis. Despite numerous advancements, more studies are to be performed to incorporate these discoveries into clinical settings, and eventually, more personalized treatments can be created.

Vascular Ehlers–Danlos syndrome (vEDS): CT and histologic findings of pleural and lung parenchymal damage

To describe CT features of lung involvement in patients with vascular Ehlers-Danlos syndrome (vEDS), a rare genetic condition caused by pathogenic variants within the COL3A1 gene, characterized by recurrent arterial, digestive, and pulmonary events. All consecutive vEDS patients referred to the national tertiary referral center for vEDS, between 2004 and 2016, were included. Chest CT scans obtained during the initial vascular work-up were reviewed retrospectively by two chest radiologists for lung involvement. Five surgical samples underwent histologic examination. Among 136 enrolled patients (83 women, 53 men; mean age 37years) with molecularly confirmed vEDS, 24 (17.6%) had a history of respiratory events: 17 with pneumothorax, 4 with hemothorax, and 3 with hemoptysis that required thoracic surgery in 11. CT scans detected lung parenchymal abnormalities in 78 (57.3%) patients: emphysema (mostly centrilobular and paraseptal) in 44 (32.3%), comparable for smokers and non-smokers; clusters of calcified small pulmonary nodules in 9 (6.6%); and cavitated nodules in 4 (2.9%). Histologic examination of surgical samples found arterial abnormalities, emphysema with alveolar ruptures in 3, accompanied by diffuse hemorrhage and increased hemosiderin resorption. In vEDS patients, identification of lung parenchymal abnormalities is common on CT. The most frequently observed CT finding was emphysema suggesting alveolar wall rupture which might facilitate the diagnostic screening of the disease in asymptomatic carriers of a genetic COL3A1 gene mutation. The prognostic value and evolution of these parenchymal abnormalities remain to be evaluated. • Patients with vEDS can have lung parenchymal changes on top of or next to thoracal vascular abnormalities and that these changes can be present in asymptomatic cases. • The presence of these parenchymal changes is associated with a slightly higher incidence of respiratory events (although not statistically significant). • Identification of the described CT pattern by radiologists and chest physicians may facilitate diagnostic screening.

Communication of genetic information to at-risk relatives during the multidisciplinary monitoring of vascular Ehlers-Danlos syndrome in a French referral clinic.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited disorder leading to arterial, digestive, and uterine complications due to pathogenic COL3A1 variants. Identification of causal variants allows family screening, provided that relatives have previously been informed, according to a 2013 French Decree. The aims of our study were to assess the communication of genetic information to at-risk relatives, the impact of diagnosis disclosure and to highlight a possible link between the experience of vEDS patients and ability to communicate about genetic information. A total of n=51 vEDS adult probands answered a questionnaire during a clinical visit. Communication to relatives was considered effective if the proband gave information to some or all first-degree relatives and considered easily achieved if it was disclosed to all relatives less than a month after the diagnosis and without difficulty. Personal and family vEDS experiences of probands were also assessed. Effective communication of information to relatives was remarkably high (98%). Siblings were the most frequently informed relatives (82%). Women informed their at-risk relatives of genetic family screening faster (p=.006) and easier (p=.004) than men. There was no difference in the disclosure of information to relatives before and after 2013 in our multidisciplinary clinic. Regarding the lived experience of vEDS patients, they felt anxious (78%) at diagnosis disclosure but also considered this diagnosis as an opportunity to start a medical follow-up (82%) putting an end to diagnosis delay. Our findings highlight for the first time that the ability to easily inform at-risk first-degree relatives is related to the relief felt during vEDS-positive diagnosis disclosure (p=.04). In order to improve the communication of genetic information to relatives, we believe that psychological support should systematically be part of the multidisciplinary monitoring, just as medical follow-up and genetic counseling.

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-α 1 chain of collagen III. Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. We created 2 mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glycine substitutions analogous to those found in patients, and we showed that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase) are major mediators of vascular pathology. Treatment with pharmacologic inhibitors of ERK1/2 or PKCβ prevented death due to spontaneous aortic rupture. Additionally, we found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, was rescued by attenuation of oxytocin and androgen signaling, respectively. Taken together, our results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.

Celiprolol Treatment of Patients With Vascular Ehlers-Danlos Syndrome

Introduction: Vascular Ehlers-Danlos syndrome (vEDS) is a monogenetic disease caused by a mutation in procollagen 3A1. Clinical manifestations are arterial ruptures and dissections, as well as spontaneous ruptures of the colon, oesophagus and uterus. Expected survival is short, in historical cohorts approximately 50 years. In 2010 a French-Belgian randomized controlled trial (RCT), including 53 patients, reported a hazard ratio of only 0.36 of arterial events if patients were treated with the betablocker celiprolol [1], combining β1-adrenoceptor antagonist and β2-adrenoceptor agonist actions. The aim of this study is to report the feasibility and early outcome of celiprolol treatment in a cohort of patients with vEDS. Methods: This is a single centre series, although patients were referred from the entire country (with a population of 10 million) for assessment of a multidisciplinary team including vascular surgeons, angiologists and clinical geneticists. A prospective database was created with data on family history, previous and future clinical events, medication and side-effects. Celiprolol was administered twice daily, and titrated up by 100 mg steps every 6 months to a maximum of 400 mg per day, according to the same protocol as in the RCT. Logistic regression was used to analyse predictors of vascular events after the start of the treatment. Results: Thirty-three patients were offered treatment with celiprolol, 2011-2018. Median follow up time was 44 (range 1-78) months. Thirty-one patients had a verified mutation on COL3A1 gene. The treatment was initiated in 31 patients, while two patients abstained. Twelve patients have reached the target dose of 400 mg daily, during follow-up, and in seven patients dose uptitration is ongoing. Eleven patients experienced one or more side effects, preventing them from reaching the target dose, and two terminated the treatment for that reason. Five cases of major vascular events occurred during the time of the treatment. The following four were fatal: 1) Rupture of the ascending aorta with cardiac tamponade, 2) Aortic rupture after type B dissection, 3) Rupture of a cerebral aneurysm with subarachnoidal bleeding, and 4) Rupture of a pulmonary artery. The fifth patient (with a major vascular event) had a rupture of the splenic artery that was treated successfully with an endovascular Amplatzer plug. The two patients who were offered treatment but decided to wait, both developed severe complications: colonic perforation in one, and type B dissection in the other. The yearly risk of a major vascular event was 5% in this cohort, quite similar to that observed in the treatment-arm in the RCT (5%), but significantly lower than in the control-arm (12%). No significant predictor of vascular events was identified by logistic regression analysis. Conclusion: Treatment with celiprolol is tolerated in most vEDS patients, but less than half achieved the target dosage of 400 mg daily, during the observation period. Despite fatal vascular events, these observations suggest that celiprolol has a protective effect in vEDS. The number of patients in the cohort, and the length of follow up, is increasing. Thus, we will be able to report more definite results in the near future. Disclosure: Nothing to disclose

Application of the 2017 criteria for vascular Ehlers-Danlos syndrome in 50 patients ascertained according to the Villefranche nosology.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder due to heterozygous pathogenic COL3A1 variants. Arterial, intestinal, and/or uterine fragility is the disease hallmark and results in reduced life expectancy. The clinical diagnosis is not always straightforward and patients' selection for molecular confirmation depends on the characteristics of applied criteria, that is, the Villefranche criteria (in use until 2017) and their revision according to the new EDS nosology. Herein, we reassessed the clinical features of 50 molecularly proven vEDS patients, diagnosed according to the Villefranche nosology between 2000 and 2016, using the 2017 classification in order to explore its clinical application. Our findings indicate that the Villefranche criteria were particularly valuable for symptomatic patients, even if with a limited specificity. Our study also suggests that the revised vEDS criteria, although expected to be more specific, might have a poorer accuracy, principally in terms of sensitivity. Both sets of criteria are less effective in presymptomatic young patients, especially in the absence of a clear-cut family history. For these patients, the careful evaluation of the cutaneous, articular, and dysmorphic features and, above all, genetic testing remain crucial to set-up proper follow-up and surveillance before catastrophic vascular and intestinal events.

Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers–Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility

PurposeThe Ehlers–Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance. MethodsClinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed. ResultsThese Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS. ConclusionThe clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study

BackgroundVascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality. ObjectivesThe authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center. MethodsAll patients with molecularly confirmed vEDS were included in a retrospective cohort study. After an initial work-up, patients were treated or recommended for treatment with celiprolol (≤400 mg/day) in addition to usual care and scheduled for yearly follow-up. vEDS-related events and deaths were collected and recorded for each patient. ResultsBetween 2000 and 2017, 144 patients (median age at diagnosis 34.5 years, 91 probands) were included in this study. After a median follow-up of 5.3 years, overall patient survival was high (71.6%; 95% confidence interval: 50% to 90%) and dependent on the type of COL3A1 variant, age at diagnosis, and medical treatment. At the end of the study period, almost all patients (90.3%) were treated with celiprolol alone or in combination. More than two-thirds of patients remained clinically silent, despite a large number (51%) with previous arterial events or arterial lesions at molecular diagnosis. Patients treated with celiprolol had a better survival than others (p = 0.0004). The observed reduction in mortality was dose-dependent: the best protection was observed at the dose of 400 mg/day versus <400 mg/day (p = 0.003). During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011. ConclusionsIn this long-term survey, vEDS patients exhibited a low annual occurrence of arterial complications and a high survival rate, on which the overall medical care seems to have a positive influence.

Spontaneous pneumothorax and hemothorax frequently precede the arterial and intestinal complications of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) is a connective tissue disorder due to defective type III collagen production and is associated with arterial rupture, spontaneous intestinal perforation, and gravid uterine rupture. Spontaneous pneumothorax and/or hemothorax (P/HTX) also occurs in vEDS patients. The temporal relation of pulmonary manifestations to arterial and intestinal complications in vEDS has not been well described. This was investigated in a multi-institutional retrospective case series of vEDS patients with confirmatory testing for COL3A1 mutation between 2000 and 2012. Data abstracted included demographics, family histories, presentation, and management of associated complications. Ninety-six cases (39% males, mean age 38.6 ± 15.5 years, range 8-79) had confirmatory testing for vEDS. P/HTX was documented in 17 (17.7%) cases. Most P/HTX preceded the diagnosis of vEDS (81%). Diagnosis of vEDS was made after arterial or intestinal complications at a mean of 7 years (range 0-26) post the initial P/HTX. In conclusion, spontaneous P/HTX is an early manifestation of vEDS frequently preceding an arterial complication or intestinal perforation. Thus, a spontaneous P/HTX in a young patient should trigger a differential diagnosis that includes vEDS. This should lead to an investigation of other vEDS features and subsequent genetic testing if vEDS features are present.

Natural history of gastrointestinal manifestations in vascular Ehlers-Danlos syndrome: A 17-year retrospective review.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder due to heterozygous mutations in the COL3A1 gene with a dominant negative effect. Spontaneous bowel perforation and intra-abdominal organ rupture are common complications of vEDS. Other gastrointestinal (GI) manifestations may occur but have not been extensively characterized. We herein describe the natural history of GI events and surgery-related complications in patients with vEDS. A retrospective review of GI events in a large cohort of molecularly proven vEDS patients was conducted, after exclusion of mild forms of the disease. Of 133 patients, 41% had a history of GI manifestations with 112 events, mean 2.0±1.3 events per patient. There was an earlier occurrence of GI events in men (P 0.008). Cumulative incidence was 58% for all patients, higher in men and in patients with splice-site variants. Recurrence of GI events was reported in more than 50% of patients. Colonic perforation was the first digestive event for 47% of patients. Of 85 GI surgeries, 37 (43%) were complicated with 43 events. Nine deaths were reported in this population. Vascular Ehlers-Danlos syndrome is characterized not only by bowel perforation but also by a wide variety of GI complications that occur in close to half (41%) of patients. The pattern of GI fragility seems more severe in males and splice-site variants. Complications of GI surgery are common and are related with tissue fragility/friability.