Chronic Pain and Joint Hypermobility: A Brief Diagnostic Review for Clinicians and the Potential Application of Infrared Thermography in Screening Hypermobile Inflamed Joints.

Joint hypermobility syndromes, particularly chronic pain associated with this condition, including Hypermobile Ehlers-Danlos Syndrome (hEDS) and Hypermobility Spectrum Disorders (HSD), present diagnostic challenges due to their multifactorial origins and remain poorly understood from biomechanical and genomic-molecular perspectives. Recent diagnostic guidelines have differentiated hEDS, HSD, and benign joint hypermobility, providing a more objective diagnostic framework. However, incorrect diagnoses and underdiagnoses persist, leading to prolonged journeys for affected individuals. Musculoskeletal manifestations, chronic pain, dysautonomia, and gastrointestinal symptoms illustrate the multifactorial impact of these conditions, affecting both the physical and emotional well-being of affected individuals. Infrared thermography (IRT) emerges as a promising tool for joint assessment, especially in detecting inflammatory processes. Thermal distribution patterns offer valuable insights into joint dysfunctions, although the direct correlation between pain and inflammation remains challenging. The prevalence of neuropathies among hypermobile individuals accentuates the discordance between pain perception and thermographic findings, further complicating diagnosis and management. Despite its potential, the clinical integration of IRT faces challenges, with conflicting evidence hindering its adoption. However, studies demonstrate objective temperature disparities between healthy and diseased joints, especially under dynamic thermography, suggesting its potential utility in clinical practice. Future research focused on refining diagnostic criteria and elucidating the underlying mechanisms of hypermobility syndromes will be essential to improve diagnostic accuracy and enhance patient care in this complex and multidimensional context.

Estimates of the excess cost burden of Ehlers-Danlos syndromes: a United States MarketScan® claims database analysis.

Introduction: Patients with Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) have significant health challenges that are well-documented, however their impact in terms of cost is not known. Our research objective was to examine the cost burden of EDS and HSD in the United States. We focused this analysis on those with commercial insurance plans. Methods: We queried the MarketScan® database for year 2021 for claims that contained an ICD-10 diagnosis code for EDS or hypermobility. Excess costs for patients in the EDS and HSD cohorts were determined by matching each patient to one patient in the database that did not have a claim for EDS or HSD and comparing total costs for the calendar year. We determined whether patients had claims for selected comorbid conditions likely to impact costs during the calendar year. Results: Sample sizes were 5,113 for adult (age ≥ 18) patients with EDS, 4,880 for adult patients with HSD, 1,059 for child (age 5-17) patients with EDS, and 2,427 for child patients with HSD. The mean excess costs were $21,100 for adult EDS patients, $11,600 for adult HSD patients, $17,000 for child EDS patients, and $11,000 for child HSD patients. EDS and HSD cohorts, both adults and children, with any of the comorbidities had greater healthcare costs. The largest difference was found in the EDS cohort with gastrointestinal comorbid conditions, with more than double the costs for adults. Discussion: We found that patients in the MarketScan database, adults and children, who had EDS or HSD had substantially higher associated excess healthcare costs than patients without EDS or HSD when considering age, sex, geographic location, and comorbidities. These disproportionate healthcare costs in this population have health policy and economic implications, including the need for rapid diagnosis, access to treatment, and accelerated research to advance treatments.

Hybridized deep learning goniometry for improved precision in Ehlers-Danlos Syndrome (EDS) evaluation.

BACKGROUND: Generalized Joint Hyper-mobility (GJH) can aid in the diagnosis of Ehlers-Danlos Syndrome (EDS), a complex genetic connective tissue disorder with clinical features that can mimic other disease processes. Our study focuses on developing a unique image-based goniometry system, the HybridPoseNet, which utilizes a hybrid deep learning model. OBJECTIVE: The proposed model is designed to provide the most accurate joint angle measurements in EDS appraisals. Using a hybrid of CNNs and HyperLSTMs in the pose estimation module of HybridPoseNet offers superior generalization and time consistency properties, setting it apart from existing complex libraries. METHODOLOGY: HybridPoseNet integrates the spatial pattern recognition prowess of MobileNet-V2 with the sequential data processing capability of HyperLSTM units. The system captures the dynamic nature of joint motion by creating a model that learns from individual frames and the sequence of movements. The CNN module of HybridPoseNet was trained on a large and diverse data set before the fine-tuning of video data involving 50 individuals visiting the EDS clinic, focusing on joints that can hyperextend. HyperLSTMs have been incorporated in video frames to avoid any time breakage in joint angle estimation in consecutive frames. The model performance was evaluated using Spearman's coefficient correlation versus manual goniometry measurements, as well as by the human labeling of joint position, the second validation step. OUTCOME: Preliminary findings demonstrate HybridPoseNet achieving a remarkable correlation with manual Goniometric measurements: thumb (rho = 0.847), elbows (rho = 0.822), knees (rho = 0.839), and fifth fingers (rho = 0.896), indicating that the newest model is considerably better. The model manifested a consistent performance in all joint assessments, hence not requiring selecting a variety of pose-measuring libraries for every joint. The presentation of HybridPoseNet contributes to achieving a combined and normalized approach to reviewing the mobility of joints, which has an overall enhancement of approximately 20% in accuracy compared to the regular pose estimation libraries. This innovation is very valuable to the field of medical diagnostics of connective tissue diseases and a vast improvement to its understanding.

An exploration of the journey to diagnosis of Ehlers-Danlos Syndrome (EDS) for women living in Australia.

INTRODUCTION: Ehlers-Danlos syndromes (EDS) is an umbrella term for a group of hereditary connective tissue disorders usually featuring hyperextensible skin, easy bruising, poor healing, and joint hypermobility. According to international Ehlers-Danlos support groups, the average time to diagnosis of this rare genetic condition is 10-12 years. Consequently, the journey to diagnosis can potentially be traumatic. This pilot study aims to explore female patients' journey to a diagnosis of EDS while living in Australia. MATERIALS AND METHODS: Over six weeks, from January to February 2023, a survey was distributed on EDS social media platforms including Facebook and LinkedIn. Ethical approval was obtained through the Ulster University Institute of Nursing and Health Research Ethics Filter Committee (FCNUR). Thematic and statistical analysis of the anonymous data was completed during March 2023. RESULTS: 152 women completed the survey. More than half of the respondents first noticed symptoms of EDS more than 15 years prior to diagnosis and more than three quarters of respondents received other diagnoses prior to their EDS diagnosis. Most respondents saw their general practitioner, a physiotherapist and/or a rheumatologist prior to being correctly diagnosed with the condition. While some respondents had positive experiences with these health professionals, many felt that they were not listened to and, after doing their own research, had to educate their health professional/s about EDS. CONCLUSION: This pilot survey demonstrated that the journey to diagnosis of EDS for women in Australia is frequently long and traumatic. Participants indicated that more EDS education and training is needed for health professionals, especially GPs, to improve the diagnostic process. IMPLICATIONS FOR PRACTICE: Participants called for their self-reported symptoms to be listened to by health professionals and to be met with empathy and an open mind instead of being dismissed. Additional education and training to health professionals about connective tissue disorders including EDS may aid earlier diagnosis in Australia.

The centrality of healthcare and education interactions - An Interpretive Phenomenological Analysis of experiences of parents of children with Ehlers-Danlos Syndrome.

BACKGROUND: Ehlers-Danlos Syndrome (EDS) is a rare group of connective tissue disorders and, as such, the diagnosis can often be delayed. While emerging research indicates that there may be adverse psychosocial consequences for the child, little is known about the processes behind such outcomes, including the psychosocial impact of this rare disease on family life. AIMS: To extend our understanding, we examined the lived experiences of parenting a child with EDS. METHODS: Four parents recruited from a specialist child development clinic participated in semi-structured interviews. Data were analysed using Interpretative Phenomenological Analysis RESULTS: Three superordinate themes were identified: (1) Challenges Associated with hEDS, (2) Interactions with Professionals and (3) "Pulling and Pacing": Life with EDS. DISCUSSION: This is one of the first qualitative studies to gain an insight into the lived experiences of parenting a child with EDS. Findings had systemic implications. Specifically, we demonstrate the need for raising awareness in health and educational professionals about how to better support families to support the child, as well as the importance of promoting effective advocacy skills in parents.

An Eye into the Aorta: The Role of Extracellular Matrix Regulatory Genes ZNF469 and PRDM5, from Their Previous Association with Brittle Cornea Syndrome to Their Novel Association with Aortic and Arterial Aneurysmal Diseases.

The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes' development of aneurysmal and dissection diseases.

Microcornea, cerebellar hypoplasia and hyperlax joints-unusual combo in rare Ehlers-Danlos syndrome-musculocontractural type 1.

Ehlers-Danlos syndrome is a group of connective tissue disorders with 14 subtypes, involving joint hyperlaxity, tissue fragility, hypertensive skin and other systemic organs with an incidence of 1 in 1 000 000 worldwide. We report a middle childhood female born of second degree consanguineous marriage with limping gait with muscle weakness, with normal development and IQ. Examination revealed microcornea, distal joint laxity of fingers and wrist, hypotonia and broad-based limping gait. Fracture dislocation right hip was managed by fixation. With the atypical neuroimaging finding of cerebellar vermis hypoplasia, exome sequencing was ordered and confirmed as Ehlers-Danlos syndrome (musculocontractural type-1). Hence, genetic counselling was done and prognosis of the child was explained.

Myocardial Infarction in Young Adults: Diagnosis Begins Through Inspection.

Spontaneous coronary artery dissection (SCAD) is an atypical cause of myocardial infarction, predominantly seen in women. Among various predisposing factors, genetic vasculopathies such as connective tissue diseases significantly contribute to SCAD. This report discusses a 36-year-old male diagnosed with vascular type Ehlers-Danlos syndrome following an anterior myocardial infarction and explores relevant literature.

Social media use by patients with hypermobile Ehlers-Danlos syndrome.

BACKGROUND: Patients with uncommon genetic conditions often face limited in-person resources for social and informational support. Hypermobile Ehlers-Danlos syndrome (hEDS) is a rare or underdiagnosed hereditary disorder of the connective tissue, and like those with similar diseases, patients with hEDS have begun to turn to social media in search of care and community. The aims of our study were to understand the usage habits and perceptions of utility of social media use for patients with hEDS in order to formulate suggestions for how clinicians may best engage these and similar patient populations about this topic. METHODS: We conducted both a quantitative survey and qualitative interviews with patients who had received a robust clinical diagnosis of hEDS. RESULTS: Twenty-four individuals completed the initial survey, and a subset of 21 of those participants completed an interview. Through thematic analysis, we identified four primary themes related to their experience with social media: (1) befriending others with their disease, (2) seeking and vetting information, (3) the risks and downsides of social media use, and (4) the desire for clinicians to discuss this topic with them. CONCLUSION: We conclude by proposing five suggestions that emerge empirically from our data. These proposals will help clinicians engage their patients regarding social media use in order to promote its potential benefits and circumvent its potential harms as they pursue support for their hereditary condition.

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.

High prevalence of gastrointestinal disorders in a large cohort of patients with joint hypermobility.

The gastrointestinal (GI) manifestations in children with hypermobile Ehlers-Danlos syndrome/joint hypermobility syndrome (hEDS/JHS) are not well described. We investigated the prevalence of GI disorders in children and young adults with hEDS/JHS through a single-center retrospective review. Demographic data, clinical history, symptoms, and diagnostic studies were reviewed. Of 435 patients with hEDS/JHS, 66% were females (age 5-28 years). We noted a high prevalence of constipation (61%), dysphagia (32%), dyspepsia and/or gastroparesis (25%), eosinophilic esophagitis (EoE) (21%), and celiac disease (4%) in our cohort. Upper endoscopy and gastric emptying scans had the highest yield to detect abnormalities. Motility studies were abnormal in 31% of the 80 patients who underwent them. Dysphagia symptoms are significantly associated with EoE. Thirty-three percent of dysphagia patients had EoE, versus 16% of non-dysphagia patients (p < 0.001). Screening hEDS/JHS patients for GI issues should be routine, with further investigations and referrals guided by identified symptoms.

Management of childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A scoping review and expert co-creation of evidence-based clinical guidelines.

OBJECTIVE: To co-create expert guidelines for the management of pregnancy, birth, and postpartum recovery in the context of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). DESIGN: Scoping Review and Expert Co-creation. SETTING: United Kingdom, United States of America, Canada, France, Sweden, Luxembourg, Germany, Italy, and the Netherlands. SAMPLE: Co-creators (n = 15) included expertise from patients and clinicians from the International Consortium on the Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders, facilitated by the Ehlers-Danlos Society. METHODS: A scoping review using Embase, Medline, the Cochrane Central Register of Controlled Trials and CINHAL was conducted from May 2022 to September 2023. Articles were included if they reported primary research findings in relation to childbearing with hEDS/HSD, including case reports. No language limitations were placed on our search, and our team had the ability to translate and screen articles retrieved in English, French, Spanish, Italian, Russian, Swedish, Norwegian, Dutch, Danish, German, and Portuguese. The Mixed Methods Appraisal Tool was used to assess bias and quality appraise articles selected. The co-creation of guidelines was based on descriptive evidence synthesis along with practical and clinical experience supported by patient and public involvement activities. RESULTS: Primary research studies (n = 14) and case studies (n = 21) including a total of 1,260,317 participants informed the co-creation of guidelines in four overarching categories: 1) Preconceptual: conception and screening, 2) Antenatal: risk assessment, management of miscarriage and termination of pregnancy, gastrointestinal issues and mobility, 3) Intrapartum: risk assessment, birth choices (mode of birth and intended place of birth), mobility in labor and anesthesia, and 4) Postpartum: wound healing, pelvic health, care of the newborn and infant feeding. Guidelines were also included in relation to pain management, mental health, nutrition and the common co-morbidities of postural orthostatic tachycardia syndrome, other forms of dysautonomia, and mast cell diseases. CONCLUSIONS: There is limited high quality evidence available. Individualized strategies are proposed for the management of childbearing people with hEDS/HSD throughout pregnancy, birth, and the postpartum period. A multidisciplinary approach is advised to address frequently seen issues in this population such as tissue fragility, joint hypermobility, and pain, as well as common comorbidities, including dysautonomia and mast cell diseases.

Airway Complications in a Patient With Ehlers-Danlos Syndrome: A Case Report.

A female patient, known to have hypermobile Ehlers-Danlos syndrome (hEDS), underwent several elective gastroscopies under sedation in different hospitals. Except for a single incident of mild laryngospasm during emergence, all procedures were uneventful. On that occasion, following the procedure in the postanesthesia care unit, the patient suffered severe airway obstruction, and standard airway rescue techniques exacerbated adequate ventilation. After the removal of all stimuli and maintaining only an indirect oxygen supply via a mask in front of her face, her airway improved, and the patient fully recovered after 17 minutes. After the gastroscopy, physical examination revealed that the patient had an extremely flexible trachea that could be completely moved outside the midline to the extreme right and left. For the subsequent procedures, an airway plan was developed in conjunction with the patient and resulted in uncomplicated perianesthetic care. This case report serves to alert readers to the risk of adverse airway events in patients with EDS and suggests an alternative approach to avoid such complications. When patients receive care in different hospitals, adequate documentation is essential and adequate preoperative assessment is crucial. This case study demonstrates the value of patient-coproduction care plans.

Fracture prevalence in children diagnosed with Ehlers-Danlos Syndrome and Generalized Joint Hypermobility.

BACKGROUND: There is limited understanding of the hypothesized association between the Ehlers-Danlos Syndromes (EDS), hypermobility and fractures in children. Despite this, EDS and hypermobility continue to be raised in the legal setting as possible causes of unexplained fractures in infants where there is a concern for physical abuse. Further understanding is needed regarding fractures in children with EDS and hypermobility. OBJECTIVE: This study assessed fracture prevalence and characteristics in children diagnosed with EDS and Generalized Joint Hypermobility (GJH). The secondary outcome was fracture prevalence in infants <1 year of age. PARTICIPANTS AND SETTING: Children aged <18 years with EDS or GJH seen in a single-center EDS clinic from April 2017 to December 2021 were included. Diagnoses were based on the 2017 international classification. Exclusion criteria were concurrent medical conditions associated with bone fragility. METHODS: This retrospective descriptive study examined variables including fracture history, fracture location, fracture type, age of sustaining fracture, and injury mechanism. Descriptive statistics were used for analysis. RESULTS: Fracture prevalence was 34.6 % (9/26, 95 % CI [16.3, 52.9]) in the EDS population and 25.4 % (15/59, 95 % CI [14.3, 36.5]) in the GJH population. No fractures occurred in infancy. Most fractures occurred in the limbs. There were no rib or skull fractures. Most fractures were the result of an identifiable injury event. CONCLUSION: In a cohort of children with formally diagnosed EDS or GJH, fractures occurred commonly in ambulatory children and generally in the limbs from identifiable events. This study does not support EDS or GJH as a cause of fractures in infancy.

Case of a 33-Year-Old Woman With Hemoptysis and Migrant Nodular Cavitary Lesions.

We describe the case of a young 33-year-old woman that was referred to our clinic for evidence of migrant cavitary nodules at CT scan, dyspnea, and blood sputum. Her physical examination showed translucent and thin skin, evident venous vascular pattern, vermilion of the lip thin, micrognathia, thin nose, and occasional Raynaud phenomenon. We prescribed another CT scan that showed multiple pulmonary nodules in both lungs, some of which had evidence of cavitation. Because bronchoscopy was not diagnostic, we decided to perform surgical lung biopsy. At histologic examination, we found the presence of irregularly shaped, but mainly not dendritic, foci of ossification that often contained bone marrow and were embedded or surrounded by tendinous-like fibrous tissue. After incorporating data from the histologic examination, we decided to perform genetic counseling and genetic testing with the use of whole-exome sequencing. The genetic test revealed a heterozygous de novo missense mutation of COL3A1 gene, which encodes for type III collagen synthesis, and could cause vascular Ehlers-Danlos syndrome.

Diagnosis and treatment of the Ehlers-Danlos syndromes in China: synopsis of the first guidelines.

BACKGROUND: The Ehlers-Danlos syndromes (EDS) are a group of rare hereditary connective tissue disorders. EDS is clinically and genetically heterogeneous and usually involves multiple systems. There are 14 subtypes of EDS with hallmark features including joint hypermobility, skin hyperextensibility, and tissue fragility. The clinical manifestations and their severity differ among the subtypes, encompassing recurrent joint dislocations, scoliosis, arterial aneurysm and dissection, and organ rupture. Challenges in diagnosis and management arise from the complexity of the disease, which is further complicated by its rarity. The development of clinical guidelines and implementation of coordinated multi-disciplinary team (MDT) approaches have emerged as global priorities. MAIN BODY: Chinese Multi-Disciplinary Working Group on the Ehlers-Danlos Syndromes was therefore established. Healthcare professionals were recruited from 25 top hospitals across China. The experts are specialized in 24 fields, including genetics, vascular surgery, dermatology, and orthopedics, as well as nursing care, rehabilitation, psychology, and nutrition. Based on GRADE methodology, the Guidelines were written by the Group supervised by methodologists, following a systemic review of all 4453 articles in PubMed published before August 9, 2023, using the search term "Ehlers Danlos". A coordinated MDT approach for the diagnosis and management of EDS is highly recommended by the Group, along with 29 specific recommendations addressing key clinical questions. In addition to the treatment plan, the Guidelines also emphasize integrating support from nursing care, rehabilitation, psychology, and nutrition. This integration not only facilitates recovery in hospital settings, but most importantly, the transition from an illness-defined life to a more "normalized" life. CONCLUSION: The first guidelines on EDS will shorten the diagnostic odyssey and solve the unmet medical needs of the patients. This article is a synopsis of the full guidelines.

Lack of Diversity in Research on Females with Ehlers-Danlos Syndromes: Recruitment Protocol for a Quantitative Online Survey.

BACKGROUND: Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders caused by fragile lax collagen. Current EDS research lacks racial and ethnic diversity. The lack of diversity may be associated with the complexities of conducting a large international study on an underdiagnosed condition and a lack of EDS health care providers who diagnose and conduct research outside of the United States and Europe. Social media may be the key to recruiting a large diverse EDS sample. However, studies that have used social media to recruit have not been able to recruit diverse samples. OBJECTIVE: This study aims to discuss challenges, strategies, outcomes, and lessons learned from using social media to recruit a large sample of females with EDS. METHODS: Recruitment on social media for a cross-sectional survey examining dyspareunia (painful sexual intercourse) in females was examined. Inclusion criteria were (1) older than 18 years of age, (2) assigned female at birth, and (3) diagnosed with EDS. Recruitment took place on Facebook and Twitter (now X), from June 1 to June 25, 2019. RESULTS: A total of 1178 females with EDS were recruited from Facebook (n=1174) and X (n=4). On Facebook, participants were recruited via support groups. A total of 166 EDS support groups were identified, 104 permitted the principal investigator to join, 90 approved posting, and the survey was posted in 54 groups. Among them, 30 of the support groups posted in were globally focused and not tied to any specific country or region, 21 were for people in the United States, and 3 were for people outside of the United States. Recruitment materials were posted on X with the hashtag #EDS. A total of 1599 people accessed the survey and 1178 people were eligible and consented. The average age of participants was 38.6 (SD 11.7) years. Participants were predominantly White (n=1063, 93%) and non-Hispanic (n=1046, 92%). Participants were recruited from 29 countries, with 900 (79%) from the United States and 124 (11%) from Great Britain. CONCLUSIONS: Our recruitment method was successful at recruiting a large sample. The sample was predominantly White and from North America and Europe. More research needs to be conducted on how to recruit a diverse sample. Areas to investigate may include connecting with more support groups from outside the United States and Europe, researching which platforms are popular in different countries, and translating study materials into different languages. A larger obstacle to recruiting diverse samples may be the lack of health care providers that diagnose EDS outside the United States and Europe, making the pool of potential participants small. There needs to be more health care providers that diagnose and treat EDS in countries that are predominantly made up of people of color as well as research that specifically focuses on these populations. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/53646.