Tissue Fragility Research Articles

A case of vascular Ehlers\u2013Danlos syndrome with a ruptured hepatic artery after surgical treatment of peritonitis caused by the perforation of the colon

BackgroundEhlers–Danlos syndrome (EDS) is an inherited disorder that causes connective tissue fragility. The vascular type of EDS (vEDS) caused by defective collagen type III production accounts for 5%–10% of all EDS cases. Patients can develop gastrointestinal or arterial ruptures, which cause poor prognosis. We report a case of a patient who experienced colonic rupture, which was immediately followed by arterial rupture.Case presentationA 40-year-old man who had been genetically diagnosed with vEDS 6 years previously was admitted to our hospital with ischemic colitis. After 3 days of conservative treatment, his abdominal pain worsened, and computed tomography (CT) revealed free air in the abdominal cavity. Pan-peritonitis due to perforation of the sigmoid colon was diagnosed. Intraperitoneal lavage and drainage and Hartmann’s operation were urgently performed. Because the patient had confirmed vEDS, we performed the surgery in a protective manner. The postoperative course was initially good, and he was transferred to the general ward 3 days after surgery. However, 5 days after surgery, massive intra-abdominal hemorrhage suddenly occurred, and contrast-enhanced CT showed an aneurysm in the common hepatic artery that had ruptured; this aneurysm was not present before surgery and was far from the surgical field. Although we considered an emergency operation, the patient suddenly experienced cardiac arrest and was unresponsive to resuscitation.ConclusionsIn cases of vEDS, vascular rupture can occur immediately after surgery for intestinal rupture. We recommend paying special attention to vascular complications in patients in their forties, as such complications are the most common causes of death.

A floppy infant without lingual frenulum and kyphoscoliosis: Ehlers Danlos syndrome case report

BackgroundEhlers-Danlos syndrome (EDS) represents a group of connective tissue disorders characterized by the fragility of the soft connective tissues resulting in widespread skin, ligament, joint, blood vessel and internal organ involvement. The clinical spectrum is highly variable in terms of clinical features, complications, severity, biochemical characteristics and genes mutations.The kyphoscoliotic type EDS (EDS VIA) is a rare variant of the disease, with an incidence of 1:100.000 live births. EDS VIA presents at birth as severe muscular hypotonia, early onset of progressive kyphoscoliosis, marked hyperelasticity and fragility of the skin with abnormal scarring, severe joint hypermobility, luxations and osteopenia without a tendency to fractures. This condition is due to a mutation in the PLOD1 gene, and less commonly in FKBP14 gene, which results in the erroneous development of collagen molecules with consequent mechanical instability of the affected tissue.Case presentationA female newborn, found to be floppy at birth, presented a remarkable physical examination for joint hypermobility, muscle weakness, hyperelastic skin, a slight curve of the spine, the absence of the inferior labial and lingual frenulum. Due to severe hypotonia, neuromuscular disorders such as Spinal Muscular Atrophy (SMA), genetic diseases such as Prader Willi syndrome (PWS), myopathies and connective tissue disorders were considered in the differential diagnosis. Targeted gene sequencing were performed for SMN1, PLOD1, FKBP14, COL6A1, COL6A2, COL6A3. The urinary lysyl and hydroxy-lysyl pyridinoline ratio was diagnostic before discovering the homozygous duplication in the PLOD1 gene, which confirmed kyphoscoliotic EDS diagnosis.ConclusionIn front of a floppy infant, a large variety of disorders should be considered, including some connective diseases. The presence at the birth of kyphoscoliosis, associated with joint hypermobility and the absence of the lingual and lower lip frenulum, should suggest an EDS.

Suicidal Behaviors in Women With the Hypermobile Ehlers–Danlos Syndrome

Background Hypermobile Ehlers–Danlos syndrome (hEDS) is the most frequent heritable disorder of the connective tissue. This is characterized by a generalized fragility of tissues leading to chronic pain, disability and high levels of psychological distress. Suicidal behaviors in those affected are not uncommon but they have not been well studied. We aimed to explore aspects of suicidality and related factors in a group of patients with hEDS. Method Thirty-five women with hEDS were included in this cross-sectional study. They were assessed with the Mini-International Neuropsychiatric Interview for Axis 1 DSM-IV mental disorders and suicidality. They also responded to self-questionnaires assessing health (pain, BMI, and diagnosis delay) and psychosocial variables (social support, physical functioning, coping strategies, personality disturbances, and resilience). Results Eleven patients (31.4%) had attempted suicide in the past. Fifteen patients (42.9%) had some degree of suicide risk at the time of evaluation, mainly mild risk (60%). Compared with patients without a history of suicide attempt, those who had attempted suicide were younger, scored higher on personality disturbances, especially on depressive, avoidant, antisocial, and borderline trait subscores, and had an increased prevalence of lifetime major depression, mania/hypomanic episodes, and anxiety disorders (p < .05). Binary logistic regression showed that personality disturbances and anxiety disorders increase the probability of belonging to the attempters group. Conclusions Consistent with previous reports, these data highlight the high frequency of suicidal behaviors in hEDS patients as well as the importance to explore psychopathology in those affected in order to identify vulnerable individuals and provide specific support. HIGHLIGHTS Attempted suicide in patients with hEDS is not uncommon. Age and the presence of psychopathology are associated with suicide attempt in hEDS patients. Personality disturbances and lifetime anxiety disorders predicted suicide attempted in this sample.

A Novel Approach for Gastric Cancer Staging in Elderly Patients Based on the Lymph Node Ratio.

PurposeTo date, no studies have been performed on staging based on the lymph node ratio (LNR) in elderly patients with gastric cancer who may require limited lymph node (LN) dissection due to morbidity and tissue fragility. We aimed to develop a new N staging system using the LNR in elderly patients with gastric cancer.Materials and MethodsThe present study included patients aged over 75 years who underwent curative gastrectomy between January 1989 and December 2018. Clinicopathological data including the number of retrieved and metastatic LNs were collected and the LNR values were obtained (LNR = the number of metastatic LNs/the number of retrieved LNs). Eleven LNR groups with intervals of 0.1 were divided into four stages based on the inflection points at which the hazard ratio (HR) increased. Survival analysis was performed to evaluate the prognostic value of the LNR.ResultsThe four LNR stages included LNR0 (n=364), LNR1 (n=128), LNR2 (n=103), and LNR3 (n=10). In the multivariate analysis, both N staging and LNR staging exhibited significant prognostic values for predicting survival outcomes. However, the incremental change in the hazard ratio (HR) between consecutive stages was greater for the LNR staging than for the N staging (HRs: 1.607, 2.758, and 3.675 for N staging; 1.583, 3.514, and 10.261 for LNR staging).ConclusionsLNR staging is more useful than N staging in predicting the prognosis in elderly patients with gastric cancer and may be used as a complement or alternative to N staging.

A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders.

Background:Ehlers-Danlos Syndromes (EDS) and Hypermobility Spectrum Disorders (HSD) are a heterogeneous group of heritable genetic connective tissue disorders with multiple characteristics including joint hypermobility, tissue fragility, and multiple organ dysfunction. Respiratory manifestations have been described in EDS patients, but have not been systematically characterized. A narrative review was undertaken to describe the respiratory presentations and management strategies of individuals with EDS and HSD.Methods:A broad literature search of Medline, Embase, Cochrane Database of Systematic Reviews, and Cochrane CENTRAL was undertaken from inception to November 2020 of all study types, evaluating EDS/ HSD and pulmonary conditions. This narrative review was limited to adult patients and publications in English.Results:Respiratory manifestations have generally been described in hypermobile EDS (hEDS), classical and vascular EDS subtypes. Depending on EDS subtype, they may include but are not limited to dyspnea, dysphonia, asthma, sleep apnea, and reduced respiratory muscle function, with hemothorax and pneumothorax often observed with vascular EDS. Respiratory manifestations in HSD have been less frequently characterized in the literature, but exertional dyspnea is the more common symptom described. Respiratory symptoms in EDS can have an adverse impact on quality of life. The respiratory management of EDS patients has followed standard approaches with thoracotomy tubes and pleurodesis for pleural manifestations, vocal cord strengthening exercises, continuous positive pressure support for sleep apnea, and exercise training. Reduced respiratory muscle function in hEDS patients responds to inspiratory muscle training.Conclusion:Respiratory symptoms and manifestations are described in EDS and HSD, and have generally been managed using conservative non-surgical strategies. Research into the prevalence, incidence and specific respiratory management strategies in EDS and HSD is needed to mitigate some of the associated morbidity.

Ehlers Danlos Syndrome with Glycosaminoglycan Abnormalities.

Ehlers-Danlos syndrome (EDS) is a genetically and clinically heterogeneous group of connective tissue disorders that typically present with skin hyperextensibility, joint hypermobility, and tissue fragility. The major cause of EDS appears to be impaired biosynthesis and enzymatic modification of collagen. In this chapter, we discuss two types of EDS that are associated with proteoglycan abnormalities: spondylodysplastic EDS and musculocontractural EDS. Spondylodysplastic EDS is caused by pathogenic variants in B4GALT7 or B3GALT6, both of which encode key enzymes that initiate glycosaminoglycan synthesis. Musculocontractural EDS is caused by mutations in CHST14 or DSE, both of which encode enzymes responsible for the post-translational biosynthesis of dermatan sulfate. The clinical and molecular characteristics of both types of EDS are described in this chapter.

They've been BITTEN: reports of institutional and provider betrayal and links with Ehlers-Danlos Syndrome patients' current symptoms, unmet needs and healthcare expectations.

Patients with rare and/or care-intensive conditions, such as Ehlers-Danlos Syndrome (EDS), can pose challenges to their healthcare providers (HCPs). The current study used the BITTEN framework1 to code EDS patients' open-ended written responses to a needs survey to determine their self-reported prevalence of healthcare institutional betrayal and its link with their expressed symptoms, provider perceptions, unmet needs, and on-going healthcare-related expectations. Patients with EDS (n = 234) were recruited via a rare disease electronic mailing list and snowball sampling. A total of one-hundred and six respondents (45.3%) endorsed having unmet healthcare-related needs; of these, 104 (99%) completed an open-ended prompt about these needs. Responses were coded for components of BITTEN, a framework designed to link patients' past, current, and future healthcare-related experiences in a trauma informed manner. Many respondents with ongoing needs endorsed experiencing past institutional and provider betrayal (43%; n = 45), current mental health symptoms (91.4%; n = 95), negative expectations for future healthcare (40.4%; n = 62), and a lack of trust in their healthcare provider (22.1%; n = 23). There were no significant differences in post-traumatic stress disorder (PTSD)/anxiety, depression/sadness, or isolative symptoms between respondents coded for institutional betrayal (n = 45) compared with those not (n = 59). However, EDS respondents reporting institutional betrayal were significantly more likely to self-report anger and irritability symptoms, a lack of trust in their HCPs, and more negative expectations for future healthcare than those not reporting institutional betrayal. The frequent spontaneous reporting of past healthcare betrayals among patients with EDS implies the need for trauma-informed care and provider education. Given that experiences of institutional betrayal are associated with increased anger and irritability, as well as with negative expectations for future healthcare interactions, efforts to repair healthcare provider and system-wide relationship ruptures might have positive healthcare consequences. Reports of Institutional and Provider Betrayal and Links with Ehlers-Danlos Syndrome Patients' Current Symptoms, Unmet Needs and Future Healthcare Expectations What is EDS? Ehlers-Danlos Syndrome (EDS) refers to a group of rare genetic connective tissue disorders that are primarily characterized by skin hyperelasticity, joint hypermobility, and tissue fragility. Connective tissue is largely responsible for the structural integrity of our bodies, and there are several EDS subtypes which each describe a specific connective tissue problem. In addition, there is significant overlap between EDS types and other kinds of connective tissue disorders. As a result, recognizing, diagnosing, and treating EDS is often challenging. What is Institutional betrayal? Institutional Betrayal here refers to a harmful action (i.e. commission) or lack of action (i.e. omission) on the part of a healthcare institution, individual provider/healthcare team, or insurance company. When a patient trusts that the healthcare system will act in their best interest, and trust is violated, institutional betrayal occurs. What is BITTEN? BITTEN is an acronym for Betrayal, Indicator, Trauma symptoms, Trust, Expectations, and Needs. It is a framework meant to capture previous problematic healthcare-related experiences in EDS patients, then to consider how those experiences influence a patient's current symptoms, provider trust, future expectations in healthcare encounters, and on-going needs. Why was this done? EDS, like many rare diseases, is hard to recognize and manage. We aim to:Give voice to EDS patients and their common unmet needs and healthcare-related expectations.Highlight how healthcare providers can apply BITTEN to improve care practices in rare disease patient encounters. What did we do? Using a newly articulated applied model of healthcare, BITTEN, we analyzed the open-ended responses of EDS patients describing their unmet emotional and mental health needs. What did we find? Nearly half of EDS patients who indicated they had unmet needs reported experiencing institutional betrayal.EDS patients who reported institutional betrayal also expressed anger, a lack of trust in healthcare providers, negative expectations for future healthcare, and more unmet needs more frequently than EDS patients who did not report institutional betrayal. What does this mean? The EDS patients in this sample were not directly asked if they had experienced institutional betrayal, so the exact prevalence is not known. Furthermore, responses were obtained voluntarily via the internet, so caution should be taken when generalizing these findings.However, results indicate that too many patients with EDS have experienced healthcare betrayals; these experiences are associated with current anger and negative expectations for future healthcare interactions.The prevalence of past negative healthcare experiences, along with current unmet needs and future negative healthcare expectations in EDS patients who have experienced institutional betrayal, highlights the need for healthcare providers to tend to these experiences, mend patient-provider barriers, and provide higher quality healthcare.

ADAMTSL2 gene variant in patients with features of autosomal dominant connective tissue disorders

Ehlers-Danlos syndrome (EDS) consists of a heterogeneous group of genetically inherited connective tissue disorders. A family with three affected members over two generations with features of Dermatosparaxic EDS (dEDS) autosomal dominant transmission was reported by Desai et al. and having a heterozygous nonsynonymous missense variant of ADAMTSL2 (c.1261G > A; p. Gly421Ser). Variation in this gene is also reported to cause autosomal recessive geleophysic dysplasia. We report five unrelated patients with the Gly421Ser variant identified from a large series of patients presenting with features of connective tissue disorders, each with a positive family history consistent with autosomal dominant transmission. Clinical features of a connective tissue disorder included generalized joint hypermobility and pain with fragility of internal and external tissues including of skin, dura, and arteries. Overall, our analyses including bioinformatics, protein modeling, and gene-protein interactions with the cases described would add evidence for the Gly421Ser variant in ADAMTSL2 as causative for variable expressivity of autosomal dominant connective tissue disorders.

Impaired Mitochondrial and Metabolic Function of Fibroblasts Derived from Patients with Recessive Dystrophic and Junctional Epidermolysis Bullosa

Background: Recessive dystrophic epidermolysis bullosa (RDEB) and junctional EB (JEB) are inherited disorders characterised by fragility and blistering of epithelial tissues leading to pain, pruritus, and adherent scarring. The severity and chronic nature of the resultant skin wounds significantly reduces quality and length of life. Current therapies primarily consist of protective bandaging and nutritional supplementation; there is no cure for these disorders. Although the skin fragility results from a lack of C7 protein (RDEB) and laminin-332 (JEB), other serious aspects of these disorders, such as inflammation that interferes with healing and aggressive squamous cell carcinoma, have not been completely elucidated. Recent research has suggested that mitochondrial function plays a significant role in skin healing. Objective: To evaluate how mitochondrial function differs in patients with RDEB and JEB. Method: The energy status of RDEB and JEB patient-derived fibroblasts was determined by Seahorse analysis and metabolite production. The energetics and overall morphology of RDEB and JEB patient-derived fibroblasts were assayed as a measure of metabolic stress. Results: EB patient-derived fibroblasts showed impaired oxidative phosphorylation with concomitant compensation by glycolysis. Morphological parameters were altered in RDEB and JEB fibroblasts compared with controls. Conclusion: This is the first study to describe changes in mitochondrial energy metabolism, metabolic profile, and mitochondrial morphology of EB patients.

Classical-like Ehlers–Danlos syndrome: a clinical description of 20 newly identified individuals with evidence of tissue fragility

PurposeCurrently, 31 patients with classical-like EDS (clEDS) due to tenascin-X deficiency have been reported in the literature. We report on the clinical and molecular characteristics of 20 additional patients with clEDS to expand knowledge and to enable improved management of this rare genetic disorder. MethodsPatients diagnosed with clEDS by the national EDS service in the UK (n=21) and abroad (n=1) were asked for consent for publication of their clinical and molecular data. ResultsOf 22 patients, 20 consented. All patients had typical features of clEDS: joint hypermobility, easy bruising, and skin hyperextensibility without atrophic scars. Importantly, 3/20 patients experienced gastrointestinal complications consisting of small or large bowel ruptures and one esophageal rupture. Other notable observations included two separate occurrences of spontaneous compartment syndrome, suspicion of nonaccidental injury due to significant bruising, and significant clinical variability regarding the debilitating effect of joint dislocations. ConclusionsWe propose a predisposition to tissue fragility, particularly of the gastrointestinal tract in patients with clEDS. As such, clinical and molecular confirmation of this diagnosis is essential. It is recommended to follow up these patients closely to understand the natural history to develop better recommendations for management.

Pain Symptomatology and Management in Pediatric Ehlers-Danlos Syndrome: A Review.

Ehlers–Danlos syndromes (EDS) are a group of connective tissue disorders that manifest with hyperextensibility of joints and skin, and general tissue fragility. While not a major criterion for clinical diagnosis, pain is a frequently endorsed symptom across subtypes of EDS. As such, the present review aims to summarize research to date on pain characteristics and management, and the relationship between such pain symptomatology and quality of life in pediatric EDS. Characteristics of pain, including theorized etiology, relative intensity and extent of pain are described, as well as descriptions of frequently endorsed pain sites (musculoskeletal, and non-musculoskeletal). Interventions related to the management of musculoskeletal (e.g., pharmaceutical intervention, physical therapy) and non-musculoskeletal pain (e.g., pharmaceutical and psychological interventions) are discussed, highlighting the need for additional research related to pediatric pain management in the context of hypermobility syndromes. In addition, the relationship between pain in pediatric EDS and quality of life is described. Finally, limitations of literature to date are described and recommendations for future lines of research are outlined.

Psychosocial Influence of Ehlers-Danlos Syndrome in Daily Life of Patients: A Qualitative Study.

(1) Background: Ehlers–Danlos syndrome is a heterogeneous group of connective tissue disorders causing pain, fatigue, and disabilities; it has several implications for patients who suffer from this disease. The major clinical manifestations of EDS include joint hypermobility, skin hyperextensibility, and generalized connective tissue fragility. This research aims to explore their perceptions and experiences about the phycological and social spheres. (2) Methods: Semistructured interviews were carried out. Participants were encouraged to talk about issues related to their disease by asking open-ended questions in one to one interview. The interview guide included questions to identify the syndrome’s influence on the social and psychological life of patients All interviews were audio recorded, fully transcribed, and analyzed using the phenomenological theoretical framework. The method of analysis was the thematic interpreting of perspectives and approaches. (3) Results: 31 individuals were proposed to participate in this study. Five patients refused to participate, so a total of 26 interviews were performed. Six themes ((1) Pain and its consequences on a daily basis; (2) The need to name the problem: the diagnosis; (3) Restructuring leisure and social relationships; (4) Limitations due to economic conditions; (5) Psychological impact of the disease situation; (6) Professional limitations) and four subthemes ((1) The value of partner support; (2) The weather influence on social plans; (3) Physical exercise and illness; (4) Support groups) emerged from the data. (4) Conclusions: This study revealed the impact of the syndrome on the social and daily life of patients, and not only in a physical level, but also in a psychological and social approach. These findings allow healthcare providers to know more about this disease in order to support and give advice to patients about the changes they will have to make.

Hypermobile Ehlers-Danlos syndromes: Complex phenotypes, challenging diagnoses, and poorly understood causes.

The Ehlers-Danlos syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. There is phenotypic and genetic variation among the 13 subtypes. The initial genetic findings on EDS were related to alterations in fibrillar collagen, but the elucidation of the molecular basis of many of the subtypes revealed several genes not involved in collagen biosynthesis or structure. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several comorbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on age, gender, lifestyle, and expression domains of the EDS genes during development and postnatal life. In this review, we summarize the current molecular, genetic, epidemiologic, and pathogenetic findings related to EDS with a focus on the hypermobile type.

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

BackgroundThe Ehlers-Danlos syndromes (EDS) are rare connective tissue disorders consisting of 13 subtypes with overlapping features including joint hypermobility, skin and generalized connective tissue fragility. Classical EDS (cEDS) is principally caused by heterozygous COL5A1 or COL5A2 variants and rarely by the COL1A1 p.(Arg312Cys) substitution. Current major criteria are (1) skin hyperextensibility plus atrophic scars and (2) generalized joint hypermobility (gJHM). Minor criteria include additional mucocutaneous signs, epicanthal folds, gJHM complications, and an affected first-degree relative. Minimal criteria prompting molecular testing are major criterion 1 plus either major criterion 2 or 3 minor criteria. In addition to these features, the clinical picture also involves multiple organ systems, but large-scale cohort studies are still missing. This study aimed to investigate the multisystemic involvement and natural history of cEDS through a cross-sectional study on a cohort of 75 molecularly confirmed patients evaluated from 2010 to 2019 in a tertiary referral center. The diagnostic criteria, additional mucocutaneous, osteoarticular, musculoskeletal, cardiovascular, gastrointestinal, uro-gynecological, neuropsychiatric, and atopic issues, and facial/ocular features were ascertained, and feature rates compared by sex and age.ResultsOur study confirms that cEDS is mainly characterized by cutaneous and articular involvement, though none of their hallmarks was represented in all cases and suggests a milder multisystemic involvement and a more favorable natural history compared to other EDS subtypes. Abnormal scarring was the most frequent and characteristic sign, skin hyperextensibility and gJHM were less common, all without any sex and age bias; joint instability complications were more recurrent in adults. Some orthopedic features showed a high prevalence, whereas the other issues related to the investigated organ systems were less recurrent with few exceptions and age-related differences.ConclusionsOur findings define the diagnostic relevance of cutaneous and articular features and additional clinical signs associated to cEDS. Furthermore, our data suggest an update of the current EDS nosology concerning scarring that should be considered separately from skin hyperextensibility and that the clinical diagnosis of cEDS may be enhanced by the accurate evaluation of orthopedic manifestations at all ages, faciocutaneous indicators in children, and some acquired traits related to joint instability complications, premature skin aging, and patterning of abnormal scarring in older individuals.

Assessing Palliative Care Needs in Patients with Ehlers-Danlos Syndrome (GP760)

• Examine ways in which palliative care is appropriate for patients with Ehlers-Danlos Syndrome.• Appraise findings from novel comprehensive assessment tool for palliative care needs in patients with Ehlers-Danlos Syndrome. Ehlers-Danlos Syndrome (EDS) is a grouping of 13 disorders affecting connective tissues, particularly collagen, characterized by tissue fragility, joint hypermobility, and hyperextensibility. EDS symptoms can include pain, dislocations, subluxations, joint instability, impaired ability to eat, and vascular symptoms. Palliative care (PC) is appropriate for patients diagnosed with EDS due to the high symptom burden of the disease and the impact of EDS on quality of life for both patients and family caregivers. However, there is a dearth of research published connecting PC and EDS. To create and pilot a PC needs assessment for patients with Ehlers-Danlos Syndrome. A prospective, pilot quantitative descriptive exploratory study using an investigator developed Likert-style online assessment based on the eight domains of quality PC. Participants were recruited through the Ehlers-Danlos International Society’s ListServ. Snowball sampling was encouraged. A total of 234 online surveys were completed. Few patients were offered PC consults (8.6%, n=19,), but those who were offered consults accepted them (89.5%, n=17). Most patients (92.6%, n=217) reported physical symptoms were not well managed. Many participants perceived having emotional or mental health needs that were not well managed (50.5%, n=107). Approximately a third of respondents perceived having needs related to advanced care planning (ACP; 38.3%, n=77), but most had not discussed ACP with their providers (86.7%, n=176). Additional domains had varying levels of need, with some patients reporting a need for each domain. Patients with EDS are not usually referred to PC. Most patients with EDS have unmet physical and psychological needs, with numerous patients reporting unmet needs in the process of care, social, and ethical/legal domains of care.

SUN-362 Bone Involvement in Adult Patients Affected with Ehlers-Danlos Syndromes

INTRODUCTION: The Ehlers-Danlos syndrome (EDS) is characterized by abnormalities of the connective tissue leading to ligamentous laxity and skin and tissue fragility, bone involvement is an emerging manifestation. We evaluated the bone metabolism, bone mineral density (BMD) and bone quality (measured by trabecular bone score, TBS), and the prevalence of clinical fractures and morphometric vertebral fractures (mVFx) in a large group of adult EDS patients. METHODS: Two-hundred and sixty-six consecutive Caucasian patients, aged ≥18 years (38.3±11.8) (190 females, 76 males) 58% with classical, 34.9% with hypermobility, 4.5% with vascular and 4.8% undefined EDS were enrolled. We had genetic information of 117 patients (74 patients showed no mutations, 2 COL2 mutations, 8 COL3 mutation, 28 COL5 mutations and 5 other genes mutations). In all subjects’ calcium-phosphorous metabolism, bone turnover, BMD at the lumbar spine (LS) and femur (femoral neck, FN and total femur, FT) and radius and TBS by dual-energy X-ray absorptiometry were assessed. Moreover, we evaluated the history of clinical fragility and the mVFx presence by spine radiograph. RESULTS: The 20.6% of patients showed a Z-score BMD ≤-2.0, the 29.8% ≥1 mVFx and the 24.5% ≥1 clinical fractures. Male patients showed a higher prevalence of reduced BMD (31.9 vs 15.6%; p=0.007) and mVFx (41.4% vs 24.8%; p=0.026). Patients with ≥1 mVFx were older (43.2±12 vs 35.6±12; p=0.0001), showed a lower TBS z-score (-1.4±1.7 vs -0.8±1.2; p=0.013) and lower phosphate levels (3.3±0.6 vs 3.5±0.5; p=0.032) with an higher prevalence of hypophosphatemia (24.5% vs 8.8%; p=0.014). No difference was found in prevalence of EDS subtypes or gene mutations. In EDS patients, the VFx presence was significantly associated with TBS and age, even after adjusting for sex and hypophosphatemia. CONCLUSIONS: EDS patients have reduced BMD and bone quality (as measured by TBS) and increased prevalence of clinical and mVFx associated with age and TBS.

Surgical Management of Shoulder and Knee Instability in Patients with Ehlers-Danlos Syndrome: Joint Hypermobility Syndrome.

Ehlers-Danlos Syndrome (EDS) is a hereditary disorder of the connective tissue, which has been classified into numerous subtypes over the years. EDS is generally characterized by hyperextensible skin, hypermobile joints, and tissue fragility. According to the 2017 International Classification of EDS, 13 subtypes of EDS have been recognized. The majority of genes involved in EDS are either collagen-encoding genes or genes encoding collagen-modifying enzymes. Orthopedic surgeons most commonly encounter patients with the hypermobile type EDS (hEDS), who present with signs and symptoms of hypermobility and/or instability in one or more joints. Patients with joint hypermobility syndrome (JHS) might also present with similar symptomatology. This article will focus on the surgical management of patients with knee or shoulder abnormalities related to hEDS/JHS.

Dental Manifestations of Ehlers-Danlos Syndromes: A Systematic Review.

Ehlers-Danlos syndromes (EDS) are a group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and variable tissue fragility. However, there are limited published data on the dental manifestations of EDS. This review systematically assessed the spectrum of published dental anomalies in various types of EDS. Twentyfour individual case reports/series and 3 longer case-control studies, reporting on a total of 84 individuals with a clinical diagnosis of EDS, were included in the data analysis. The main dental features listed in classical EDS were pulp calcification and localized root hypoplasia. Common dental abnormalities observed in vascular EDS were pulp shape modifications (52.2%), exceeding root length (34.8%), and molar root fusion (47.8%). Dentinogenesis imperfecta is a consistent finding in osteogenesis imperfecta/EDS overlap syndrome. Data on dental manifestations in other types of EDS are both rare and generally inconclusive.

Outcomes of transcatheter aortic-valve implantation in patients receiving chronic systemic corticosteroid treatment

The chronic use of systemic corticosteroid (CS) therapy is associated with greater tissue fragility. Data assessing the effects of this treatment on the results of transcatheter aortic-valve implantation (TAVI) are scarce. To describe the impact of chronic use of CS treatment on early and late outcomes after TAVI. All 1299 consecutive patients undergoing TAVI in our institution between October 2006 and November 2018 were included. Their mean age was 81 ± 10 years, 52.4% were male, their median EuroSCORE 2 was 4.7% (2.8–7.5). Among them, 48 (3.7%) received chronic systemic CS treatment at the time of the procedure and were compared to those without CS. Patients with chronic CS therapy tended to be women (60% vs. 47%, P = 0.078) and needed more frequently dialysis (12.5% vs. 2.6%, P = 0.002). All other baseline clinical and echocardiographic characteristics were similar between both groups. No differences were observed in 30-day mortality (6.2% vs. 4.3%, P = 0.46). However, after adjustment, patients in the CS group had more frequent major vascular complications (16.7% vs. 7.4%, hazard ratio (HR) 2.52, 95%Confidence Interval (CI) 1.14–5.9; P = 0.02), major or life-threatening bleedings (22.9% vs. 12.4%, HR 2.02, 95%CI 1.00–4.08; P = 0.05) and tamponades (8.3% vs. 2.4%, HR 4.05, 95%CI 1.35–12.15, P < 0.001) at 30 days than those in the non-CS group. At 1-year, all-cause mortality was significantly higher in CS group than in the non-CS group (37.5% vs. 12.6%, p-log rank < 0.0001). Multivariate analysis confirmed that chronic use of CS was an independent predictor of 1-year all-cause mortality (HR 2.29, 95%CI: 1.16–4.50, P = 0.017) ( Fig. 1 ). Chronic systemic CS treatment was associated with an increase in major or life-threatening bleedings, major vascular complications and tamponades at 30 days and was an independent predictor of 1-year all-cause mortality. This treatment should be taken into account in the risk stratification of TAVI candidates.

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome.

Musculocontractural Ehlers–Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1 (CHST14/D4ST1, mcEDS-CHST14), or in the gene for dermatan sulfate epimerase (DSE, mcEDS-DSE). Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous (Chst14−/−) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies.