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Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β1-adrenoceptor antagonist with a β2-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptitrated every 6 months by steps of 100 mg to a maximum of 400 mg per day. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15–0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

Introduction The Hypermobile Online Pain managemEnt (HOPE) programme is a stakeholder informed intervention adopting the biopsychosocial pain approach, specifically for people with hypermobile Ehlers–Danlos Syndrome (hEDS) and hypermobility spectrum disorder (HSD) experiencing pain. The programme topics included were based on a modified Delphi of a large sample of stakeholders: people with hEDS/HSD and healthcare practitioners who are experienced with managing these conditions. Programme feasibility, acceptability and appropriateness were previously evaluated quantitatively in a pilot randomised controlled trial, but the in‐depth experiences and perceptions of participants who engaged with the programme is unknown. Methods Qualitative study. 1:1, semi‐structured online interviews of participants who took part in the HOPE programme. Data was analysed using an inductive thematic analysis approach as described by Braun and Clark. Results Twelve participants were interviewed; 91% were female, mean age 38.1 (SD 9.1). Four themes emerged: (1) The biopsychosocial approach to understanding pain used in the HOPE programme was acceptable and appropriate, (2) benefits of the programme were stronger for those who were newer on their hEDS/HSD journey, (3) self‐guided reflections included in the programme required headspace and personal meaning and (4) participants desired more adaptable content and programme functionality. Additionally, participants gave suggestions on how to improve the content, adherence and engagement to the programme. Conclusion The HOPE programme was considered feasible, acceptable and appropriate for people with hEDS/HSD. The four themes and suggestions from our study findings will be used to refine subsequent versions and large‐scale trials of the HOPE programme, as well as provide translatable insights for other online interventions for hEDS/HSD or similar complex, chronic multisystemic conditions. Patient or Public Contribution A large community of hEDS/HSD patients' and healthcare providers' input were obtained from a two‐staged online Delphi from a prior study. This approach was preferred to capture the greatest amount of feedback from a diverse international voice. Via the Delphi study, they provided suggestions for content topics and consensus on what they felt were important to include in a hEDS/HSD specific online pain management programme, as well as programme parameters (e.g., duration and frequency of programme; healthcare provider telehealth component; types of learning activities).

Mutations in the COL1A1 and COL1A2 genes, encoding the proα1 and 2 chains of type I collagen, cause osteogenesis imperfecta (OI) or Ehlers‐Danlos syndrome (EDS) arthrochalasis type. Although the majority of missense mutations in the collagen type I triple helix affect glycine residues in the Gly‐Xaa‐Yaa repeat, few nonglycine substitutions have been reported. Two arginine‐to‐cysteine substitutions in the α1(I)‐collagen chain are associated with classic EDS [R134C (p.R312C)] or autosomal dominant Caffey disease with mild EDS features [R836C (p.R1014C)]. Here we show α1(I) R‐to‐C substitutions in three unrelated patients who developed iliac or femoral dissection in early adulthood. In addition, manifestations of classic EDS in Patient 1 [c.1053C>T; R134C (p.R312C); X‐position] or osteopenia in Patients 2 [c.1839C>T; R396C (p.R574C); Y‐position] and 3 [c.3396C>T; R915C (p.R1093C); Y‐position] are seen. Dermal fibroblasts from the patients produced disulfide‐bonded α1(I)‐dimers in ∼20% of type I collagen, which were efficiently secreted into the medium in case of the R396C and R915C substitution. Theoretical stability calculations of the collagen type I heterotrimer and thermal denaturation curves of monomeric mutant α1(I)‐collagen chains showed minor destabilization of the collagen helix. However, dimers were shown to be highly unstable. The R134C and R396C caused delayed procollagen processing by N‐proteinase. Ultrastructural findings showed collagen fibrils with variable diameter and irregular interfibrillar spaces, suggesting disturbed collagen fibrillogenesis. Our findings demonstrate that R‐to‐C substitutions in the α1(I) chain may result in a phenotype with propensity to arterial rupture in early adulthood. This broadens the phenotypic range of nonglycine substitutions in collagen type I and has important implications for genetic counseling and follow‐up of patients carrying this type of mutation. Hum Mutat 28(4), 387–395, 2007. © 2007 Wiley–Liss, Inc.

The Ehlers-Danlos Syndrome (EDS) is a heritable connective tissue disorder characterized by hyperextensible skin, joint hypermobility and soft tissue fragility. The classic subtype of EDS is caused by mutations in one of the type V collagen genes (COL5A1 and COL5A2). Most mutations affect the type V collagen helical domain and lead to a diminished or structurally abnormal type V collagen protein. Remarkably, only two mutations were reported to affect the extended, highly conserved N-propeptide domain, which plays an important role in the regulation of the heterotypic collagen fibril diameter. We identified a novel COL5A1 N-propeptide mutation, resulting in an unusual but severe classic EDS phenotype and a remarkable splicing outcome. We identified a novel COL5A1 N-propeptide acceptor-splice site mutation (IVS6-2A>G, NM_000093.3_c.925-2A>G) in a patient with cutaneous features of EDS, severe progressive scoliosis and eye involvement. Two mutant transcripts were identified, one with an exon 7 skip and one in which exon 7 and the upstream exon 6 are deleted. Both transcripts are expressed and secreted into the extracellular matrix, where they can participate in and perturb collagen fibrillogenesis, as illustrated by the presence of dermal collagen cauliflowers. Determination of the order of intron removal and computational analysis showed that simultaneous skipping of exons 6 and 7 is due to the combined effect of delayed splicing of intron 7, altered pre-mRNA secondary structure, low splice site strength and possibly disturbed binding of splicing factors. We report a novel COL5A1 N-propeptide acceptor-splice site mutation in intron 6, which not only affects splicing of the adjacent exon 7, but also causes a splicing error of the upstream exon 6. Our findings add further insights into the COL5A1 splicing order and show for the first time that a single COL5A1 acceptor-splice site mutation can perturb splicing of the upstream exon.

Background Ehlers–Danlos syndrome (EDS) is a heterogeneous group of heritable connective tissue disorders with varying features depending on the EDS subtype. EDS is associated with various respiratory manifestations. Pulmonary hemorrhage has been previously reported in vascular EDS (vEDS); however, this manifestation remains not particularly well-defined in other subtypes of EDS. This study extends the clinical understanding of EDS, particularly non-vascular EDS, and expands etiological spectrum of pulmonary hemorrhage in children. Methods We retrospectively analyzed the records of patients diagnosed with EDS between January 2020 and November 2024 at our institute. All clinical data was extracted from the electronic medical records, including clinical presentation, physical examination, family history, and chest computed tomography scans. EDS was confirmed based on clinical manifestations, pathological biopsies, immunohistochemistry, immunofluorescence staining, and genetic testing. Results Our study identified eight patients with EDS who presented with pulmonary hemorrhage. Among these eight patients, nine gene mutations were identified, including four in COL3A1 , two in COL1A1 , one in COL1A2 , one in TNXB , and one in COL4A2 . We identified the mutations: IVS44 + 1G→A and c.1550 C > T (p. Pro517Leu) of COL3A1 gene as two novel mutations associated with vEDS. And we added pathogenic evidences of the mutations c.1550 C > T (p. Pro517Leu) and c.3133G > A (p. Ala1045Thr) in COL3A1 gene. Conclusions Two novel and two pathogenic mutations in COL3A1 gene associated with vEDS, COL1A1 , COL1A2 , TNXB gene mutations of non-vascular types underlying EDS and COL4A2 gene associated with collagen synthesis were found in patients presenting with pulmonary hemorrhage. These findings would enhance clinical recognition of EDS and provide a sound basis to recommend that children with pulmonary hemorrhage be routinely examined for joint and skin hyperextension.

Purpose: The purpose of this study was to characterize the nature and magnitude of pregnancy risks in women with vascular Ehlers–Danlos syndrome. Methods: Pregnancy-related death rate was determined by a review of pedigrees of families with vascular Ehlers–Danlos syndrome. Maternal morbidity was characterized through semistructured interviews with women with vascular Ehlers–Danlos syndrome or their next of kin. Results: Pregnancy-related deaths occurred in 30 of 565 deliveries (5.3%). There was no difference in Kaplan–Meier survival curves between parous versus nulliparous women with vascular Ehlers–Danlos syndrome. Interviews with 39 women indicated that 46% of deliveries were uncomplicated. The most common pregnancy-related complications were third-/fourth-degree lacerations (20%) and preterm delivery (19%). Life-threatening complications occurred in 14.5% of deliveries and included arterial dissection/rupture (9.2%), uterine rupture (2.6%), and surgical complications (2.6%). There were 5 maternal deaths in 76 deliveries (6.5%). Conclusion: The risk of pregnancy-related complications is increased in women with vascular Ehlers–Danlos syndrome compared with the general population; however, survival data indicate that pregnancy does not appear to affect overall mortality compared with nulliparous women with vascular Ehlers–Danlos syndrome. The data were insufficient to determine whether mode or timing of delivery influenced risk of complications. Women with vascular Ehlers–Danlos syndrome should be engaged in a shared decision-making process when contemplating pregnancy and pregnancy management. Genet Med 16 12, 874–880.

Hypermobility spectrum disorders (HSD) affect individuals across physical, psychological and social domains, making assessment and management difficult. Management for this condition primarily focuses on addressing the musculoskeletal complaints using physiotherapy rather than the additional manifestations such as fatigue, anxiety and depression. This systematic review aims to identify psychological interventions and assess whether they improve the lived experiences of individuals with HSD. It also aims to assess which psychological interventions were most effective, which symptoms were most effectively managed by a psychological intervention, and whether there were differences between children and adults. Studies were included if they were a randomised controlled trial or pre/post-test design, a sample of any age and clinical diagnosis of HSD (including Ehlers-Danlos syndrome), used a psychological intervention and assessed the effect of the intervention on lived experiences using appropriate outcome measures. Risk of bias was assessed using the Mixed Methods Appraisal Tool. The results were narratively synthesised. Six studies were included in the review, one isolated psychological intervention and five incorporated a psychological intervention within a multidisciplinary programme. The interventions predominantly aimed to reduce pain including intensity, interference, pain-related fear and catastrophising, with anxiety and depression, affect, daily living, fatigue also being evaluated. The most beneficial psychological interventions were those delivered alongside physiotherapy in an outpatient or community setting, improving both the physical and psychological aspects of pain, subsequently improving quality of life. However, there lacks randomised controlled trials with larger samples to definitively confirm the significant findings discussed in this review.

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.

BackgroundWhile an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55–200 repeats) of the FMR1 gene may be overlooked.ObjectiveTo report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.MethodsWe collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS.ResultsFive cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity.ConclusionBoth hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

Spinal deformity in Ehlers–Danlos syndrome (EDS) is an important symptom that can lead to trunk balance deterioration, respiratory dysfunction, and digestive disorders as the deformity progresses, thereby reducing a patient’s quality of life and activities of daily living. The severity of the deformity varies widely, with treatment depending on the extent and the presence of associated complications. The present review addressed the current state of clinical research and treatment of spinal deformities in EDS with a specific focus on the musculocontractural type. Further studies are needed to better understand the underlying mechanisms of spinal deformity in EDS.