Despite celiprolol therapy, patients with vascular Ehlers-Danlos syndrome remain at risk of vascular events: A 12-year experience in an Italian referral center.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol has been suggested to significantly reduce rates of vascular events in this setting, though real-world evidence is limited. The aim of this study was to report our experience with celiprolol therapy in vEDS management. METHODS: Patients with a genetically confirmed diagnosis of vEDS who were referred for outpatient consultation at the Brescia University Hospital between January 2011 and July 2023 were included. At each visit, patients' medical history, results of vascular imaging, and office blood pressure measurements were recorded. Celiprolol therapy was progressively titrated to the maximum tolerated dose of up to 400 mg daily, according to the patients' tolerance. RESULTS: Overall, 26 patients were included. Female sex was prevalent (62%). Mean (SD) age was 37 (16) years. Follow-up duration was 72 (41) months. At the last follow-up visit, all patients were on celiprolol therapy, 80% of whom were taking the maximum recommended dose. The yearly risk of symptomatic vascular events was 8.8%, the majority of which occurred after reaching the maximum recommended dose of celiprolol. No significant predictor of symptomatic vascular events was identified among patients' clinical characteristics. CONCLUSION: In our cohort, rates of celiprolol use were high and the drug was well tolerated overall. Nonetheless, the risk of symptomatic vascular events remained nonnegligible. Future studies should identify reliable predictors of major adverse events and explore additional therapeutic strategies that could further lower the risk of life-threatening events in this population.

Vascular Ehlers-Danlos syndrome and pregnancy: A systematic review.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder associated with an elevated risk of vascular, uterine and digestive complications. Managing pregnancy in this context can be a challenge. OBJECTIVES: To systematically review the literature data on the complications in pregnancy associated with vEDS. SEARCH STRATEGY: We searched the Pubmed Medline and Embase databases for articles using the following terms "vascular Ehlers-Danlos syndrome" or "vEDS" AND "pregnancy". SELECTION CRITERIA: Women with vEDS. DATA COLLECTION AND ANALYSIS: We searched the PubMed® MEDLINE® database for publications evaluating obstetric outcomes in women with vEDS. MAIN RESULTS: A total of 121 publications were screened, with six (accounting for 412 pregnancies) included in our review. Of the women included in this sample, 30% were infertile. The miscarriage rate was 13.8% (57/412) and 8.8% of the live births were premature. Obstetric anal sphincter injuries occurred in 11.3% (23/203) of the deliveries. The maternal mortality rate per pregnancy was 5.7%. CONCLUSIONS: Women with vEDS present an elevated risk of uterine rupture, vascular events, digestive events and death during pregnancy. Women appear to be most at risk during the peripartum period; to avoid expulsive efforts, a caesarean section should be scheduled at 37 weeks of gestation.

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.

Splenic artery pathology presentation, operative interventions, and outcomes in 88 patients with vascular Ehlers-Danlos syndrome.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (VEDS) is rare and associated with arteriopathies. The aim of this study is to investigate the presentation, operative interventions, and outcomes of splenic arterial pathology in a population of more than 1500 individuals with genetically confirmed VEDS due to pathogenic COL3A1 variants. METHODS: Cross-sectional analysis of 1547 individuals was performed. The data were assembled by harmonizing data from three overlapping cohorts with genetically confirmed VEDS: the VEDS Collaborative Natural History Study (N = 242), a single-center cohort (N = 75), and the University of Washington Collagen Diagnostic Lab cohort (N = 1231). Duplicates were identified and removed. Patients were selected for analysis if they had splenic artery aneurysm (SAA), pseudoaneurysm, dissection, thrombosis, or rupture. Demographics, COL3A1 variants, interventions, and outcomes were analyzed. Comparisons by splenic artery rupture were made. RESULTS: A total of 88 patients presented between 1992 and 2021 with splenic artery pathology (5.7% of the cohort; mean age at diagnosis, 37 ± 11.1 years; 50% male). One-third were diagnosed with VEDS prior to the splenic artery pathology diagnosis, and 17% were diagnosed post-mortem. Most had a positive family history (61%). Most had COL3A1 variants associated with minimal normal collagen production (71.6%). Median follow up was 8.5 years (interquartile range, 0.9-14.7 years). Initial presentation was rupture in 47% of the cases. Splenic artery rupture overall was 51% (n = 45), including four cases of splenic rupture. There were no major differences in VEDS-related manifestations or COL3A1 variant type by rupture status. SAA was noted in 39% of the cases. Only 12 patients had splenic artery diameter documented in 12 cases with a median diameter of 12 mm (interquartile range, 10.3-19.3 mm). A total of 34 patients (38.6%) underwent 40 splenic arterial interventions: 21 open surgical, 18 embolization, and one unknown procedure. More than one splenic artery intervention was performed in five cases (14.7%). Open repair complications included arteriovenous fistula (n = 1), intestinal or pancreatic injury (n = 1 each), and four intraoperative deaths. There were no deaths or access site complications related to splenic artery embolization. Four patients (23.5%) developed a new SAA in the remaining splenic artery post embolization. All-cause mortality was 35% (n = 31), including 22 related to a ruptured splenic artery. CONCLUSIONS: Splenic arteriopathy in VEDS is associated with variants that affect the structure and secretion of type III collagen and frequently present with rupture. Rupture and open repair are associated with high morbidity and mortality, whereas embolization is associated with favorable outcomes. Suggest repair considerations at SAA diameter of 15 mm. Long-term follow-up is indicated as secondary splenic arteriopathy can occur.

Comprehensive genetic screening for vascular Ehlers-Danlos syndrome through an amplification-based next-generation sequencing system.

Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys-Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.

Vascular Ehlers-Danlos syndrome with a Novel missense COL3A1 gene mutation present with bilateral spontaneous carotid-cavernous fistula: a case report.

This report describes a unique case of vascular Ehlers-Danlos syndrome (vEDS) characterized by multiple spontaneous direct carotid-cavernous sinus fistulas (CCF). The patient initially presented with ocular symptoms and was effectively treated with transarterial coil embolization. Five years later, the patient developed recurrent contralateral CCF that required complex endovascular techniques. Genetic testing identified a novel mutation in the COL3A1 gene, confirming the diagnosis of vEDS. This case report provides a near-term perspective on the identification of structural abnormalities in the COL3A1 protein to ensure the safety of endovascular therapy for patients with vEDS.

[Gastric pyloric stenosis caused by submucosal hematoma in a patient with vascular type Ehlers-Danlos syndrome:a case report].

Ehlers-Danlos syndrome (EDS) is a relatively rare syndrome characterized by excessive stretching of the skin and joints and hemorrhage and increased tissue fragility due to abnormal collagen. Particularly, vascular type EDS has been associated with type III collagen-rich aorta and intestinal tract fragility, owing to which young people are at a risk of spontaneous arterial rupture, aneurysm, aortic dissection, and gastrointestinal perforation. However, there have been few reports regarding gastric submucosal hematoma caused by EDS. Herein, we presented the case of a 29-year-old man who was diagnosed with EDS during his childhood and used to attend another hospital. He visited our hospital after developing epigastralgia and vomiting. The patient presented with pyloric stenosis caused by gastric antrum submucosal hematoma as revealed via abdominal contrast-enhanced computed tomography (CT), esophagogastroduodenoscopy (EGD), and endoscopic ultrasonography. He was admitted and underwent conservative therapy in addition to fasting, drip infusion, and tube feeding. The follow-up CT and EGD revealed hematoma shrinkage, after which he was discharged as no further deterioration was observed. Thus, based on the observed EDS characteristics, an accurate diagnosis is warranted to avoid unnecessary invasive therapy.

Generation of the human induced pluripotent stem cell line (IBKMOLi003-A) from PBMCs of a vascular Ehlers-Danlos syndrome (vEDS) patient carrying the heterozygous nonsense mutation c.430C > T (p.Q105*) in the COL3A1 gene.

Ehlers-Danlos syndrome (EDS) belongs to a spectrum of rare heritable connective tissue disorders and is characterised by hyperextensibility, joint hypermobility and tissue fragility. Peripheral blood mononuclear cells (PBMCs) from a vascular EDS (vEDS) patient, known as the rarest EDS subtype, carrying a heterozygous nonsense mutation c.430C > T (p.Q105*) in the COL3A1 gene, which is essential for type III collagen synthesis, were reprogrammed into induced pluripotent stem cells (iPSCs). The generated iPSCs exhibit high expression of pluripotency-associated markers, possess trilineage differentiation capacity and reveal a normal karyotype. This novel patient-specific cell line enables in-depth pathophysiological studies of vEDS.

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.

Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. METHODS: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. RESULTS: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). CONCLUSIONS: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.

Internal carotid artery dissection associated with an elongated hyoid bone in a patient with vascular Ehlers-Danlos syndrome.

Hyoid bone-related carotid injury is a rare cause of neurovascular events. This report describes a case of a young, healthy male presenting with neck pain followed by left-sided hemiparesis. The patient was diagnosed with a transient ischaemic attack attributed to structural damage of the vascular surface of the right internal carotid artery as a direct result of continuous compression by an elongated hyoid bone. We describe a successful diagnosis using a series of manoeuvres during a six-vessel cerebral angiogram. Genetic testing later confirmed the diagnosis of vascular Ehlers-Danlos syndrome.

Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome.

Background Arterial tortuosity is associated with adverse events in Marfan and Loeys-Dietz syndromes but remains understudied in Vascular Ehlers-Danlos syndrome. Methods and Results Subjects with a pathogenic COL3A1 variant diagnosed at age <50 years were included from 2 institutions and the GenTAC Registry (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions). Height-adjusted vertebral artery tortuosity index (VTI-h) using magnetic resonance or computed tomography angiography was calculated. Associations between VTI-h and outcomes of (1) cardiovascular events (arterial dissection/rupture, aneurysm requiring intervention, stroke), or (2) hollow organ collapse/rupture at age <50 years were evaluated using receiver operator curve analysis (using outcome by age 30 years) and mixed-effects Poisson regression for incidence rate ratios. Of 65 subjects (54% male), median VTI-h was 12 (interquartile range, 8-16). Variants were missense in 46%, splice site in 31%, and null/gene deletion in 14%. Thirty-two subjects (49%) had 59 events, including 28 dissections, 5 arterial ruptures, 4 aneurysms requiring intervention, 4 strokes, 11 hollow organ ruptures, and 7 pneumothoraces. Receiver operator curve analysis suggested optimal discrimination at VTI-h ≥15.5 for cardiovascular events (sensitivity 70%, specificity 76%) and no association with noncardiovascular events (area under the curve, 0.49 [95% CI, 0.22-0.78]). By multivariable analysis, older age was associated with increased cardiovascular event rate while VTI-h ≥15.5 was not (incidence rate ratios, 1.79 [95% CI, 0.76-4.24], P=0.185). However, VTI-h ≥15.5 was associated with events among those with high-risk variants <40 years (incidence rate ratios, 4.14 [95% CI, 1.13-15.10], P=0.032), suggesting effect modification by genotype and age. Conclusions Increased arterial tortuosity is associated with a higher incidence rate of cardiovascular events in Vascular Ehlers-Danlos syndrome. Vertebral tortuosity index may be a useful biomarker for prognosis when evaluated in conjunction with genotype and age.

Fatigue in patients with syndromic heritable thoracic aortic disease: a systematic review of the literature and a qualitative study of patients' experiences and perceptions.

INTRODUCTION: The purpose of this study was to explore the literature on fatigue in patients with syndromic heritable thoracic aortic disease (sHTAD), including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), vascular Ehlers Danlos syndrome (vEDS) and other sHTADs, critically appraise and synthesize the relevant literature. We also aimed to investigate how adults with sHTAD experience and perceive fatigue, and to discuss clinical implications and direction for further research. METHODS: First, a systematic review was performed by searching the published literature in all relevant databases and other sources until 20th October 2022. Second, a qualitative focus group interview study was conducted of 36 adults with sHTADs (LDS n = 11, MFS n = 14, vEDS n = 11). RESULTS: In the systematic review, 33 articles satisfied the eligibility criteria (3 reviews and 30 primary studies). Of the primary studies: 25 dealt with adults (MFS n = 17, MFS/EDS n = 1, EDS n = 2, LDS/vEDS n = 3, different sHTADs n = 2), 5 with children (MFS n = 4, different sHTADs n = 1). Twenty-two were cross-sectional quantitative studies, 4 prospective and 4 qualitative studies. The quality of the included studies was mostly good, but many had small sample sizes, low response rates and/or participants without verified diagnosis. Despite these limitations, studies indicated high prevalence of fatigue (ranging from 37 to 89%), and fatigue was associated with both health and psychosocial aspects. Few studies found that fatigue was associated with disease-related symptoms. In the qualitative focus groups most of the participants reported that they had experienced fatigue which influenced several aspects of life. Four themes related to fatigue were elucidated: (1) different diagnoses-different fatigue?, (2) the nature of fatigue, (3) searches for causes of fatigue, (4) dealing with fatigue in daily life. The four themes seemed mutually interrelated in terms of barriers, strategies and facilitators for dealing with fatigue. The participants experienced fatigue as a consistent dilemma between self-assertion and inadequacy. Fatigue seems to influence several aspects of daily life and may be one of the most debilitating symptoms of having a sHTAD. CONCLUSION: Fatigue seems to negatively impact the lives of people with sHTADs and should be recognized as an important aspect in the lifelong follow-up of these patients. The life-threatening complications of sHTADs may result in emotional stress, including fatigue and the risk of developing a sedentary lifestyle. Research and clinical initiatives should consider rehabilitation interventions aiming at postponing the onset or reducing symptoms of fatigue.

Identification of two novel COL3A1 variants in patients with vascular Ehlers-Danlos syndrome.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant disease caused by aberrations in COL3A1, which encodes type III collagen. Sanger sequencing has limitations for diagnosis since exon deletion/duplication and splicing alterations are not uncommon in COL3A1. We report 2 patients with vEDS who were not diagnosed by conventional Sanger sequencing. METHODS: We performed either targeted panel or whole-genome sequencing. Complementary DNA (cDNA) sequencing was performed using cultured skin fibroblasts. Sanger sequencing of DNA was performed for the confirmation of breakpoints in the case of exon deletion. We also evaluated the sensitivity of the splicing prediction tool, SpliceAI. RESULTS: An exon 27 deletion was suspected on targeted panel sequencing of 1 patient. The deletion was confirmed using cDNA sequencing (r.1870_1923del) and breakpoints were confirmed (c.1870-109_1923+10del). On targeted panel sequencing in the other patient, we found a novel intronic variant of c.1149+6T>C that leads to skipping of exon 16 (r.1051_1149del) by cDNA sequencing. SpliceAI showed 98.8% sensitivity for known splicing variants in COL3A1. CONCLUSION: Our study highlights the necessity of a comprehensive approach to the genetic diagnosis of vEDS. In addition, cDNA sequencing was useful as an auxiliary method, especially considering the limited sensitivity of the splicing prediction tool.

Genetic Basis, New Diagnostic Approaches, and Updated Therapeutic Strategies of the Syndromic Aortic Diseases: Marfan, Loeys-Dietz, and Vascular Ehlers-Danlos Syndrome.

Syndromic aortic diseases (SADs) encompass various pathological manifestations affecting the aorta caused by known genetic factors, such as aneurysms, dissections, and ruptures. However, the genetic mutation underlying aortic pathology also gives rise to clinical manifestations affecting other vessels and systems. As a consequence, the main syndromes currently identified as Marfan, Loeys-Dietz, and vascular Ehlers-Danlos are characterized by a complex clinical picture. In this contribution, we provide an overview of the genetic mutations currently identified in order to have a better understanding of the pathogenic mechanisms. Moreover, an update is presented on the basis of the most recent diagnostic criteria, which enable an early diagnosis. Finally, therapeutic strategies are proposed with the goal of improving the rates of patient survival and the quality of life of those affected by these SADs.

The dysmorphic phenotype in vascular Ehlers Danlos syndrome.

The Ehlers Danlos syndromes are identified by their connective tissue features and are not rich in dysmorphic handles. Vascular Ehlers Danlos syndrome (vEDS) however, is characterised by a recognisable phenotypic constellation of internal and external dysmorphology. This review charts the paediatric and adult phenotypes of vEDS due primarily to COL3A1 gene variants and the potential recognition of some other EDS subtypes, including COL1A1 and COL25A1 that can present with vEDS-like features, with certain dysmorphic handles as clues to the diagnosis and the adjunct of gene testing in patients presenting with vEDS features.