Ehlers-Danlos Syndrome Hypermobility Type Research Articles

Pseudogene TNXA Variants May Interfere with the Genetic Testing of CAH-X.

CAH-X is a hypermobility-type Ehlers-Danlos syndrome connective tissue dysplasia affecting approximately 15% of patients with 21-hydroxylase deficiency (21-OHD) congenital adrenal hyperplasia (CAH) due to contiguous deletion of CYP21A2 and TNXB genes. The two most common genetic causes of CAH-X are CYP21A1P-TNXA/TNXB chimeras with pseudogene TNXA substitution for TNXB exons 35-44 (CAH-X CH-1) and TNXB exons 40-44 (CAH-X CH-2). A total of 45 subjects (40 families) from a cohort of 278 subjects (135 families of 21-OHD and 11 families of other conditions) were found to have excessive TNXB exon 40 copy number as measured by digital PCR. Here, we report that 42 subjects (37 families) had at least one copy of a TNXA variant allele carrying a TNXB exon 40 sequence, whose overall allele frequency was 10.3% (48/467). Most of the TNXA variant alleles were in cis with either a normal (22/48) or an In2G (12/48) CYP21A2 allele. There is potential interference with CAH-X molecular genetic testing based on copy number assessment, such as with digital PCR and multiplex ligation-dependent probe amplification, since this TNXA variant allele might mask a real copy number loss in TNXB exon 40. This interference most likely happens amongst genotypes of CAH-X CH-2 with an in trans normal or In2G CYP21A2 allele.

Health-Related Quality of Life and Psychological Distress in Patients With Hypermobility Type Ehlers-Danlos Syndrome

Patients with Ehlers-Danlos Syndrome, hypermobile type (hEDS) often report a decrease of health-related quality of life (HRQoL), symptoms of anxiety and depression, and show a prevalent incidence of psychiatric disorders. Still, there seems to be a lack of a more thorough analysis addressing the relations between these entities. We studied the HRQoL and its relations with depressive symptoms and subgroups of anxiety in a group of patients with hEDS ( n = 81) compared to a comparison group ( n = 90) of healthy controls (HC). HRQoL was assessed with the RAND 36-item health survey, depressive symptoms were measured with the 21-item Beck Depression Inventory (BDI-II) and State/trait anxiety inventory (STAI) was used to estimate levels of state and trait anxiety. The hEDS group showed significantly lower scores on total HRQoL, on all subscales as well on calculated subgroups of physical and mental HRQoL than the HC group. Depression, state, and trait anxiety scores were significantly higher in hEDS group than in the HC group. However, both state and trait anxiety showed a lower degree of negative associations with social functioning in the hEDS group when compared to the HC group. Patients with hEDS present with a lower HRQoL and greater psychological distress than healthy individuals. These factors play a significant role in the patients’ overall functional capacity and should be noticed when examining and treating patients with hEDS.

Psychosocial and Motor Characteristics of Patients With Hypermobility

ObjectivesTo identify psychosocial and motor aspects related to joint hypermobility (JH) in a sample from almost all Brazilian states by age range and sex; to characterize JH by the Beighton total score ≥4, ≥5, and ≥6 according to sex and age and atypicality in the sitting position and in the hands; identify, in the total sample, manifestations of “growing pain” and its location, fatigue, attention deficit, anxiety, insomnia, drowsiness, apathy, depression, delay in walking, not crawling or crawling differently, school performance, spatial orientation and/or temporally impaired, social isolation, and being stigmatized as “lazy/clumsy/apathetic”.MethodsThis retrospective, observational, quantitative, and cross-sectional study used data obtained through analyses of descriptive and inferential crossings between 2012 and 2020 of 482 medical records of individuals between 1 and 76 years of age, from most Brazilian states. All patients previously diagnosed with “joint hypermobility syndrome” (JHS) and “Ehlers-Danlos syndrome hypermobility type” (EDS-HT) had their medical records reassessed, following the guidelines established in 2017. The analysis of GJH was performed using the updated method by Beighton method; atypical characteristics were investigated in the hands and the ability to sit in the “W” and the “concave” positions. The characteristics and manifestations of “growing pain” and its location were analyzed in the total sample, fatigue, insomnia, drowsiness, apathy, depression, social isolation, attention deficit, anxiety, stigmatization as “lazy,” clumsy/restless, impaired school performance, and spatial and/or temporal orientation. Descriptive and inferential statistical methods were used, such as Mean, Median, Mode, Standard Deviation, Standard Error, Maximum Value, Minimum Value, Komolgorov-Smirnov, Significance, Relative Value, Absolute Value, Mann-Whitney U, and Correlation of Spearman.ResultsJH in the total sample predominated in the upper limbs, the majority were women, represented by 352 (73.02%), 15 years old or older with 322 (66.80%), 312 (64.73%) had a Beighton total score ≥6, which decreased as the age increased. Always sitting in the “concave” position was represented by 54.15% and the ability to sit in the “W” position by 39.21%; signs on the hands totaled between 27.59 and 44.19% with a significant correlation between the variables. Among the characteristics, fatigue predominated, followed by an awkward/clumsy/restless individual, attention deficit, anxiety and stigmatized as “lazy,” insomnia, drowsiness, apathy, depression, impaired spatial and/or temporal orientation, and social isolation. From the total sample, pain in the lower limbs was reported by 55.81% and having or having had “growing pain” was reported by 36.93%, delay in walking occurred in 19.92%, 15.35% did not crawl or crawled differently, and for 12.86%, school performance was impaired. Higher Beighton total scores showed a trend towards motor implications and correlation between variables. Ability to still sit in the “concave” position was possible for 54.15% and to sit in the “W” position for 39.21%.ConclusionIn the total sample, the JH characteristic prevails in the upper limbs of female children, adolescents and adults, with a total Beighton score ≥6. Most sit in the “concave” position and less than half also sit in the “W” position and with atypical hand postures. The higher Beighton scores, which include the upper limbs, show a tendency to not crawl or crawl differently, delayed ambulation, and impaired school performance. The predominance of JH in the upper limbs is suggestive of a justification for not crawling or crawling differently. Characteristics of atypical motor performance in hands and sitting posture, in addition to fatigue, pain since childhood, anxiety, apathy, depression, sleep disorders, stigmatization, attention deficit, spatial and/or temporal orientation impairment, and social isolation are characteristics. suggestive of psychosocial implications at different ages. Future studies with motor and psychosocial aspects of people with JH will help to identify the phenotype of this population and consequent guidance for clinical management based on the motor and psychosocial aspects of people with JH.

Healthcare utilization among youth with Ehlers-Danlos syndrome hypermobile type.

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited disorders of connective tissue. EDS hypermobility type (EDS-HT), characterized by joint hypermobility, is most common and increasingly recognized in pediatrics. Treatment involves protecting joints, preventing injuries, and managing symptoms/comorbidities. Pediatric EDS-HT patients often see multiple medical providers; however, data on healthcare utilization (HCU) in this population are lacking. This retrospective, electronic chart review examines HCU data 1 year prior and subsequent to a new diagnosis of EDS-HT using Villefranche criteria. Demographics, diagnoses, and HCU (office visits, therapies, hospital encounters/procedures, and tests) were obtained for N=102 youth attending a Connective Tissue Disorder Clinic over a 21-month timeframe. After EDS-HT diagnosis, HCU patterns shifted to reflect greater involvement of therapy (physical, psychological, and occupational) and symptom management. More genetics, rheumatology, and orthopedics visits occurred prediagnosis, and more physical therapy, pain management, cardiology, and neurology visits occurred postdiagnosis. Testing and hospital encounter/procedure frequencies did not change. Overall, the pattern of HCU changed from diagnostic to treatment, in accordance with evidence-based EDS-HT care. Understanding HCU patterns of pediatric patients with EDS-HT can elucidate patient interaction with the health care system, with the potential to inform and improve the standard of care.

What are the most important symptoms to assess in hypermobile Ehlers-Danlos syndrome? A questionnaire study based on the Delphi technique

Purpose This study aims to determine from questionnaires, submitted to patients with Ehlers-Danlos syndrome hypermobile type (hEDS), what symptoms they perceive as having the most impact on their well-being and, according to them, what symptoms should be assessed. Materials and methods Three rounds of online questionnaires were conducted following the Delphi method. The first round allowed us to obtain the most important symptoms to assess according to the patients. The second and third round aimed at ranking the categories according to their order of importance. Establishment of a consensus was evaluated using Kendall’s coefficient of concordance. Results A total of 118 responses were analyzed for the first round and 87 for the second and the third round. Ten categories were extracted from the first round. Ranking of the 10 categories in the second round did not reach consensus (W = 0.33, p < 0.001) nor did the four most important categories in the third round (W = 0.43, p < 0.001). However, three categories stand out from ranking: “pain”, “fatigue and sleep disorders”, and “musculoskeletal disorders”. Conclusions These categories seem to be the most important to assess in patients with hEDS, despite the lack of consensus on this ranking. Implications for rehabilitation Pain, fatigue and sleep disorders, and musculoskeletal disorders should be given high consideration in the assessment of patients with hypermobile Ehlers-Danlos syndrome (EDS). The high phenotypic variability in the hypermobile EDS requires individualized assessment for each patient and a multidisciplinary approach.

Perioperative Management of Ehlers-Danlos Type III Syndrome Associated With Postural Orthostatic Tachycardia in Patients Undergoing General Anesthesia

Ehlers-Danlos syndrome (EDS) is an autosomal dominant inherited disorder of connective tissue with common clinical features of skin hyperelasticity, joint hypermobility, and easy bruising. Postural orthostatic tachycardia syndrome (POTS) refers to more than three months of a sustained increase in heart rate of more than 30 beats per minute and symptoms of orthostatic intolerance within 10 minutes of assuming a standing position without associated hypotension. These medical conditions can be associated with each other, potentially creating significant perioperative challenges. This paper describes two cases of young women with POTS and EDS hypermobility type (III) who presented for surgery under general anesthesia. The anesthesiologist performed an extensive preoperative evaluation, provided adequate preoperative hydration, ensured careful positioning during anesthetic induction, and avoided neck hyperextension during intubation. Gentle emergence and extubation were practiced with vigilance towards complications of cervical subluxation and airway mucosal injury. Robust communication between postoperative caregivers was prioritized. All these considerations facilitated the achievement of good outcomes. Here, a literature review and subsequent flow diagram of the anesthetic management and perioperative considerations for these patients is purposed.

Autism Spectrum Disorder and Ehlers-Danlos Syndrome - Hypermobility Type: A Case Report

Introduction: Autism Spectrum Disorder (ASD) and Ehlers-Danlos Syndrome – Hypermobility type (EDS-HT) can occur concomitantly, with the overlap of the characteristics of both conditions. Early diagnosis helps prevent suffering and injuries in patients with these conditions. Objective: To report the case of an adolescent with severe autism and EDS-HT, with musculoskeletal and extra-skeletal manifestations, and how it may affect the patient´s life of and his family. Case Report: This report shows the clinical history of the signs and symptoms of EDS-HT, mainly evidenced by generalized pain, fatigue, dislocations and motor disability, due to Joint Hypermobility (JH). These manifestations may not be noticed by the family members and health professionals, due to the communicative impairment that is part of the manifestations related to ASD. Conclusion: The early identification of signs and symptoms of EDS-HT in childhood could enable a better understanding of its manifestations in patients with ASD. It also enables the prevention of joint dislocations and the proposition of a proper ergonomic design for the home environment to minimize suffering of the patient and his family.

Pelvic Girdle Pain, Hypermobility Spectrum Disorder and Hypermobility-Type Ehlers-Danlos Syndrome: A Narrative Literature Review.

Pelvic girdle pain (PGP) refers specifically to musculoskeletal pain localised to the pelvic ring and can be present at its anterior and/or posterior aspects. Causes such as trauma, infection and pregnancy have been well-established, while patients with hypermobile joints are at greater risk of developing PGP. Research exploring this association is limited and of varying quality. In the present study we report on the incidence, pathophysiology, diagnostic and treatment modalities for PGP in patients suffering from Hypermobility Spectrum Disorder (HSD) and Hypermobility-Type Ehlers-Danlos Syndrome (hEDS). Recommendations are made for clinical practice by elaborating on screening, diagnosis and management of such patients to provide a holistic approach to their care. It appears that this cohort of patients are at greater risk particularly of mental health issues. Moreover over, they may require a multidisciplinary approach for their management. Ongoing research is still required to expand our understanding of the relationship between PGP, HSD and hEDS by appropriately diagnosing patients using the latest updated terminologies and by conducting randomised control trials to compare outcomes of interventions using standardised patient reported outcome measures.

Impact of heritable disorders of connective tissue on daily life of children: Parent perspectives.

The aim of this study was to investigate parent perspectives on how heritable disorders of connective tissue (HDCT) affect a child's everyday life. In addition, this study aimed to determine if parents seeking health professional services perceive their children with HDCT to have difficulties with activities reliant on hand function. This cross-sectional study used a questionnaire for parents to explore the impact of an HDCT on a child's ability to carry out everyday activities. Parents of children (8-18 years) attending a tertiary connective tissue dysplasia clinic, over a 12-month period, were invited to participate. We analysed 100 surveys completed by parents. Children with Ehlers-Danlos syndrome-hypermobile type, joint hypermobility syndrome (48%) and osteogenesis imperfecta (42%) were the largest diagnostic groups represented. Pain (73%) and fatigue (68%) were the most common symptoms parents perceived to affect day-to-day activities. More parents were satisfied with their child's self-care (61%) than school participation (33%). Keeping up with handwriting (71%) and gross motor activities (70%) were the most frequently reported difficulties at school. Most parents (65%) reported leisure activity difficulties, with pain (64%) and fatigue (60%) as the main contributing factors. This study has provided new knowledge about the concerns of parents with their child's engagement in everyday life including the impact of HDCT on hand function. Further research is needed on effective management strategies to reduce symptoms and improve hand function for these children.

Psychiatric Disorder in Postural Orthostatic Tachycardia Syndrome and Ehlers-Danlos Syndrome-Hypermobility Type.

Postural orthostatic tachycardia syndrome (POTS) and Ehlers-Danlos syndrome-hypermobility type (EDS-HT) are disorders that have a strong association and share a relationship with some mental illnesses. Both are commonly misdiagnosed as mental disorders possibly because they share a similar phenomenology to some. There is limited awareness and recognition of POTS and EDS-HT, which subsequently delays diagnosis. The presence of an underlying mental disorder can complicate the diagnosis and management of an already challenging case, which can cause further strain to patients and their loved ones whose lives have already been destabilized significantly. National support groups have been established to support during the stressful periods of diagnosis and adjustment. In this article, the evidence for the various mental disorders that have been linked to POTS and EDS-HT is reviewed, while highlighting the need to satisfactorily screen for mental disorders in this patient group.​.

Peripheral nerve blocks in children and adolescents with Ehlers-Danlos syndrome hypermobility type

Ehlers-Danlos syndrome hypermobility type (EDS-HT) is a hereditary connective tissue disease characterized by joint hypermobility and is associated with joint dislocations and chronic pain often improved by surgery.[1][1] Peripheral nerve...

The Prevalence of the Chimeric TNXA/TNXB Gene and Clinical Symptoms of Ehlers-Danlos Syndrome with 21-Hydroxylase Deficiency.

Defects in both CYP21A2 and TNXB genes can cause congenital adrenal hyperplasia combined with hypermobility-type Ehlers-Danlos syndrome (EDS), which has recently been named CAH-X syndrome. The purpose of this study is to assess the prevalence of the chimeric TNXA/TNXB gene and clinical symptoms in a Chinese cohort with 21-hydroxylase deficiency (21-OHD). A total of 424 patients with 21-OHD who were genetically diagnosed were recruited for this study. Multiplex ligation-dependent probe amplification and sequencing were used to identify the CAH-X genotype. Clinical features of joints, skin, and other systems were evaluated in 125 patients. Ninety-four of the 424 patients had a deletion on at least 1 allele of CYP21A2 and 59 of them harbored the heterozygotic TNXA/TNXB chimera. Frequencies of CAH-X CH-1, CH-2, and CH-3 were 8.2%, 3.1%, and 2.6%, respectively. The incidences of clinical features of EDS were 71.0% and 26.6% in patients with the chimeric TNXA/TNXB genes or without (P < .001). There were statistically significant differences in manifestations among articular (P < .001 in generalized hypermobility) and dermatologic features (P < .001 in hyperextensible skin, P = .015 in velvety skin and P = .033 in poor wound healing). The prevalence of generalized hypermobility was more common in CAH-X CH-2 or CH-3 than CH-1 patients (60% vs 20%, P = .028). In summary, about 14% of patients with 21-OHD may have chimeric TNXA/TNXB gene mutations in our study and most of them showed EDS-related clinical symptoms. The correlation between CAH-X genotypes and clinical features in connective tissue, like joint or skin, needs to be further investigated.

Подходы к диагностике и ведению пациентов с гипермобильным типом синдрома Элерса — Данло

This review provides information about the patterns of the pathogenesis, clinical picture of Ehlers-Danlos syndrome (EDS), as well as the diagnosis and treatment of hypermobile type. Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited autosomal dominant diseases characterized by the development disorder of the collagen molecular structure, which leads to joint hypermobility, hyperelastic skin and its vulnerability, as well as advanced fragility of the entire body’s tissues. The clinical picture of EDS hypermobile type is dominated by musculoskeletal signs, characterized by joint hypermobility, arthralgias, dorsalgias, spontaneous joint dislocations in combination with hyperelastic skin and its vulnerability. The criteria presented in the 2017 EDS clinical classification are applied in order to make a diagnosis. Timely diagnosis of the hypermobile type of EDS syndrome contributes to early detection of changes in other organs and systems: aortic root dilation, mitral valve prolapse, abdominal hernias, pelvic organ prolapse, and others. Treatment methods include medication, physiotherapy, and surgery, the individual choice of which depends on the specific disease manifestations, the intensity and duration of pain. Competent selection of examination methods and treatment for patients with EDS hypermobil type can effectively stop chronic pain of the musculoskeletal syndrome and prevent severe disabling complications concerning internal organs.KEYWORDS: joint hypermobility, chronic pain, Ehlers-Danlos syndrome, hyperelastic skin, spontaneous dislocations, arthralgia.FOR CITATION: Viktorova I.A., Ivanova D.S., Kochimov R.Sh., Adyrbayev A.M. Methods for the diagnosis and management of patients with hypermobile Ehlers-Danlos syndrome. Russian Medical Inquiry. 2020;4(8):498–503. DOI: 10.32364/2587-6821-2020-4-8-498-503.

1518 Malone Antegrade Continence Enema for Treatment of Adult Slow Transit Constipation in Ehlers-Danlos Syndrome

INTRODUCTION: Ehlers-Danlos syndrome hypermobility type (EDS-HT) is a multisystem disorder characterized by joint and spine hyperextensibility that may also involve the gastrointestinal (GI) tract resulting in various motility disorders. The Malone antegrade continence enema (MACE) procedure is most commonly used to treat severe constipation in children with neurogenic bowel disorders. We describe a case of severe EDS-HT related refractory constipation in an adult that was treated with the MACE procedure. CASE DESCRIPTION/METHODS: 22-year-old female with history of EDS-HT and mast cell activation disorder presented to our clinic for evaluation of chronic constipation, food regurgitation, nausea, and vomiting. Workup included a gastric emptying study showing gastroparesis, a colonic transit study showing slow transit, anorectal manometry showing a weak anal sphincter but no signs of dyssynergic defecation, and a proctogram showing normal emptying with a weak pelvic floor and excessive descent. Clinical course was complicated by recurrent attacks of nausea, vomiting, and abdominal pain without evidence of obstruction resulting in repeated emergency room visits. Chronic constipation was attributed to dysmotility from EDS-HT. Various combinations of osmotic and stimulant laxatives were utilized with inadequate response. She elected to undergo MACE procedure. Her symptoms gradually resolved after the procedure and she started having one bowel movement daily with a simplified bowel regimen including once daily antegrade enemas. DISCUSSION: The pathophysiology of GI dysmotility in EDS-HT is not completely understood but possible mechanisms include altered biomechanical properties and gut neurodevelopmental changes from extracellular matrix abnormalities. The MACE procedure involves laparoscopic placement of an appendicocecostomy tube to allow daily enema administration at the level of the cecum (Figure 1). This procedure is most commonly utilized in children with neurogenic bowel disorders but should also be considered in adult EDS-HT patients with constipation refractory to medical therapy. This case highlights the potential for severe morbidity in EDS-HT-related GI dysmotility disorders and sheds light on the therapeutic potential of the MACE procedure in this patient population.

Measurement of Serum Tenascin-X in Joint Hypermobility Syndrome Patients.

Joint hypermobility syndrome (JHS) (also termed hypermobility type Ehlers-Danlos syndrome, hEDS) is a heritable connective tissue disorder that is characterized by generalized joint hypermobility, chronic pain, fatigue, and minor skin changes. Initially, it was reported that there is a small subset of patients with JHS/hEDS who have haploinsufficiency of tenascin-X (TNX). However, the relationship between TNXB and JHS/hEDS has not been reported at all afterwards. EDS was reclassified into thirteen types in 2017, and the causative gene of JHS/hEDS remained to be identified. Therefore, in this study in order to determine whether JHS/hEDS can be diagnosed by the concentrations of serum form of TNX (sTNX), we measured the concentrations of sTNX in 17 JHS/hEDS patients. The sTNX concentrations in half of the JHS/hEDS patients were significantly lower than those in healthy individuals. No mutations, insertions or deletions were detected in the TNX exon sequence of the JHS/hEDS patients except for one in patient. That patient has a heterozygous mutation. A correlation between sTNX concentration and mutation of the TNXB genomic sequence was not found in the JHS/hEDS patients. These results indicate that the decrease in sTNX concentration could be used as a risk factor for JHS/hEDS.

Understanding the psychosocial impact of joint hypermobility syndrome and Ehlers–Danlos syndrome hypermobility type: a qualitative interview study

Purpose Little attention has been paid to psychosocial factors in Joint Hypermobility Syndrome and Ehlers–Danlos Syndrome (hypermobility type). This study sought to identify the psychosocial impact by examining participants’ lived experiences; and identify characteristics of effective coping. Materials and methods Adults with Joint Hypermobility Syndrome and Ehlers–Danlos Syndrome (Hypermobility Type) were invited to discuss their own lived experiences and the impact of the condition. All met recognized criteria for clinically significant joint hypermobility, and had a self-confirmed diagnosis. The transcripts were coded and analyzed using inductive thematic analysis. Results Seventeen participants (14 women, 3 men) purposively selected to broadly represent different genders, ages and ethnicities. Analysis identified five key themes: healthcare limitations, a lack of awareness of Joint Hypermobility, and Ehlers–Danlos Syndrome (Hypermobility Type) among healthcare professionals; a restricted life; social stigma; fear of the unknown; and ways of coping. Conclusions The results highlight the significant psychosocial impact on participants’ lives. Coping approaches identified included acceptance, building social networks, learning about joint hypermobility, and adapting activities. Physiotherapists supported regular exercise. Further research should consider potential interventions to improve information provision, address psychological support, and increase awareness of hypermobility among healthcare professionals. Implications for rehabilitation Participants who had help from family members to complete activities described guilt and shame, highlighting the need for a greater rehabilitation focus on maintaining independence. Difficulties with sexual relationships due to prolapse or erectile dysfunction, and associated anxieties have indicated a need for greater awareness of these issues within primary care. The provision of reliable information and materials is vital, both for healthcare professionals and patients, to reduce misinformation and fear. Physiotherapists with knowledge of Joint Hypermobility Syndrome and Ehlers–Danlos Syndrome hypermobility type were cited as sources of support and hope, which helped people to cope with and manage their condition.

High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia

Many patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency have CAH-X syndrome, a connective tissue dysplasia consistent with hypermobility-type Ehlers-Danlos syndrome due to a contiguous gene deletion involving the adjacent CYP21A2 and TNXB genes. CAH-X syndrome is caused by carrying CYP21A1P-TNXA/TNXB chimeric genes [CAH-X chimera 1 (CH-1) and chimera 2 (CH-2)] on one or more alleles. Genetic analysis is cumbersome due to pseudogene interference. We developed a PCR-based CAH-X high-throughput screening method to assess the copy numbers of TNXB exons 35 and 40; this method is amenable to either real-time quantitative PCR or droplet digital PCR (ddPCR). The assay was validated in a cohort of 278 subjects from 146 unrelated CAH families. Results were confirmed by a validated Sanger sequencing platform. A total of 44 CAH-X-positive calls were made, with 42 (26 CH-1 and 16 CH-2) confirmed. The assay had 100% sensitivity (42 true/42 positives), 99.2% specificity (234 true/236 negatives), and an overall 99.3% accuracy (276/278). Calls made by real-time quantitative PCR and ddPCR were consistent (100%), and ddPCR offered easier data interpretation. The CAH-X prevalence was 15.6% (21/135 probands), higher than the previously estimated 8.5%, and was particularly high (29.2% or 21/72) in those with a 30-Kb deletion. This assay is suitable for high-throughput CAH-X screening, especially in subjects testing positive for CAH in neonatal screening.

391 Validating causative mutations in patients with Ehlers-Danlos Syndrome using a novel xenograft model

The Ehlers-Danlos Syndrome (EDS) is a connective tissue disease characterized by joint hypermobility and cutaneous fragility. EDS is primarily caused by mutations in fibrillar collagens or genes involved in collagen synthesis. However, in many typical cases, causative genetic defects of EDS cannot be identified, and treatment options for patients are limited to symptomatic care. The lack of appropriate in vitro and in vivo EDS models that faithfully recapitulate the clinical phenotype of the disease further complicates studies of EDS mechanisms and hampers progress toward developing efficient therapeutic strategies for the disease. To develop a clinically relevant EDS model, we focused on a cohort of patients with hypermobility type of EDS who did not harbor known EDS-associated mutations but exhibited classical symptoms of the disease. We grafted fibroblasts, isolated from a skin biopsy of one of these patients together with healthy keratinocytes onto an immunocompromised mouse to recapitulate the EDS skin phenotype in a xenograft model. We found that grafts formed with EDS fibroblasts exhibited a disorganized collagen network, which has previously been observed in the skin of EDS patients. Using RNA sequencing analysis, we also compared transcriptional profile of EDS fibroblasts with that of control cells and identified several promising mutations and transcript variants that may be causing the phenotype in our patients. To validate the candidate mutations, we have reprogrammed EDS fibroblasts into induced pluripotent stem cells (iPSCs) and are currently correcting these candidate mutations using CRISPR/Cas9. The corrected EDS iPSCs will be differentiated into fibroblasts and grafted in our xenograft assay. If the disorganized collagen network is no longer observed in the xenograft, the candidate mutation is indeed the cause of EDS in our patients, validating the usefulness of our model in identifying the mechanisms of EDS.

Safety of Endoscopy in Heritable Connective Tissue Disorders.

Little is known about the gastrointestinal manifestations or safety of endoscopy among patients with heritable connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome (EDS). We conducted an electronic cross-sectional survey nested within preexisting registries of patients with heritable connective tissue disorders and examined self-reported rates of endoscopic complications. The rate of endoscopy-related perforation was 9.4% (95% confidence interval 2.0%-25.0%) among individuals with vascular EDS, <1% in classical and hypermobility-type EDS, and zero in Marfan syndrome (P < 0.001). Spontaneous intestinal perforation was also significantly higher in the vascular EDS group. Clinicians should consider noninvasive screening methods for patients with vascular EDS.

Prevalence and frequency of self-perceived systemic features in people with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type.

Some commonly reported systemic features of joint hypermobility syndrome (JHS)/Ehlers-Danlos syndrome hypermobility type (EDS-HT) are absent from nosologies due to insufficient validity. The primary aim was to examine the hypothesised high prevalence and frequency of orthostatic intolerance, easy bruising, and urinary incontinence in adults with JHS/EDS-HT and secondarily to determine the association between extent of generalised joint hypermobility (GJH) and these systemic features. A cross-sectional cohort study was conducted via online recruitment of medically diagnosed JHS/EDS-HT patients. A survey collected demographic data and clinical history. A subgroup of participants underwent physical testing of GJH using the Beighton score and Lower Limb Assessment Score (LLAS). Descriptive analysis was performed on demographic data and self-reported non-musculoskeletal systemic features. Correlation of GJH scores and systemic features were performed using Spearman's rank correlation. The survey was completed by 116 individuals (95% female; 16-68years) with 57 (93% female) also participating in the physical assessment. The most prevalent systemic feature was orthostatic intolerance (98%), followed by easy bruising and urinary incontinence (97% and 84% respectively). Of those reporting symptoms of orthostatic intolerance, easy bruising, and urinary incontinence, 58%, 40%, and 18% described them as very highly frequent respectively (frequency > 75%). No significant correlations were found between the extent of systemic features and GJH scores as measured by either the Beighton score or the LLAS. The high prevalence and frequency of the systemic features found in this study, which are omitted in diagnostic classification criteria, suggest that further research on their diagnostic accuracy is warranted.