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The mind is embodied; thoughts and feelings interact with states of physiological arousal and physical integrity of the body. In this context, there is mounting evidence for an association between psychiatric presentations and the expression variant connective tissue, commonly recognised as joint hypermobility. Joint hypermobility is common, frequently under-recognised, significantly impacts quality of life, and can exist in isolation or as the hallmark of hypermobility spectrum disorders (encompassing joint hypermobility syndrome and hypermobile Ehlers-Danlos syndrome). In this narrative review, we appraise the current evidence linking psychiatric disorders across the lifespan, beginning with the relatively well-established connection with anxiety, to hypermobility. We next consider emerging associations with affective illnesses, eating disorders, alongside less well researched links with personality disorders, substance misuse and psychosis. We then review related findings relevant to neurodevelopmental disorders and stress-sensitive medical conditions. With growing understanding of mind-body interactions, we discuss potential aetiopathogenetic contributions of dysautonomia, aberrant interoceptive processing, immune dysregulation and proprioceptive impairments in the context of psychosocial stressors and genetic predisposition. We examine clinical implications of these evolving findings, calling for increased awareness amongst healthcare professionals of the transdiagnostic nature of hypermobility and related disorders. A role for early screening and detection of hypermobility in those presenting with mental health and somatic symptoms is further highlighted, with a view to facilitate preventative approaches alongside longer-term holistic management strategies. Finally, suggestions are offered for directions of future scientific exploration which may be key to further delineating fundamental mind-body-brain interactions.

Hypermobile Ehlers-Danlos syndrome (hEDS), mainly characterized by generalized joint hypermobility and its complications, minor skin changes, and apparently segregating with an autosomal dominant pattern, is still without a known molecular basis. Hence, its diagnosis is only clinical based on a strict set of criteria defined in the revised EDS nosology. Moreover, the hEDS phenotypic spectrum is wide-ranging and comprises multiple associated signs and symptoms shared with other heritable or acquired connective tissue disorders and chronic inflammatory diseases. In this complex scenario, we previously demonstrated that hEDS patients' skin fibroblasts show phenotypic features of myofibroblasts, widespread extracellular matrix (ECM) disarray, perturbation of ECM-cell contacts, and dysregulated expression of genes involved in connective tissue architecture and related to inflammatory and pain responses. Herein, the cellular proteome of 6 hEDS dermal myofibroblasts was compared to that of 12 control fibroblasts to deepen the knowledge on mechanisms involved in the disease pathogenesis. Qualitative and quantitative differences were assessed based on top-down and bottom-up approaches and some differentially expressed proteins were proofed by biochemical analyses. Proteomics disclosed the differential expression of proteins principally implicated in cytoskeleton organization, energy metabolism and redox balance, proteostasis, and intracellular trafficking. Our findings offer a comprehensive view of dysregulated protein networks and related pathways likely associated with the hEDS pathophysiology. The present results can be regarded as a starting point for future in-depth investigations aimed to decipher the functional impact of potential bioactive molecules for the development of targeted management and therapies.

Background Four out of five patients with hypermobility spectrum disorder (HSD) or hypermobile Ehlers-Danlos syndrome (hEDS) experience shoulder complaints including persistent pain and instability. Evidence suggests that patients with HSD/hEDS who experience knee and back complaints improve with exercise-based therapy. However, no study has focused on exercise-based treatment for the shoulder in this patient group. The potential benefits of strengthening the shoulder muscles, such as increased muscle-tendon stiffness, may be effective for patients with HSD/hEDS who often display decreased strength and increased shoulder laxity/instability. The primary aim is to investigate the short-term effectiveness of a 16-week progressive heavy shoulder strengthening programme and general advice (HEAVY) compared with low-load training and general advice (LIGHT), on self-reported shoulder symptoms, function, and quality of life. Methods A superiority, parallel group, randomised controlled trial will be conducted with 100 patients from primary care with HSD/hEDS and shoulder complaints (persistent pain and/or instability) for more than 3 months. Participants will be randomised to receive HEAVY (full range of motion, high load) or LIGHT (neutral to midrange of motion, low load) strengthening programme three times weekly with exercises targeting scapular and rotator cuff muscles. HEAVY will be supervised twice weekly, and LIGHT three times during the 16 weeks. The primary outcome will be between-group difference in change from baseline to 16-week follow-up in the Western Ontario Shoulder Instability Index (WOSI, 0-2100 better to worse). Secondary outcomes will include a range of self-reported outcomes covering symptoms, function, and quality of life, besides clinical tests for shoulder strength, laxity/instability, and proprioception. Outcome assessors will be blinded to group allocation. Participants will be kept blind to treatment allocation through minimal information about the intervention content and hypotheses. Primary analyses will be performed by a blinded epidemiologist. Discussion If effective, the current heavy shoulder strengthening programme will challenge the general understanding of prescribing low-load exercise interventions for patients with HSD/hEDS and provide a new treatment strategy. The study will address an important and severe condition using transparent, detailed, and high-quality methods to potentially support a future implementation. Trial registration ClinicalTrials.gov NCT03869307. Registered on 11 March 2019.

There is an association between joint hypermobility, hypermobile Ehlers-Danlos syndrome (hEDS) and different forms of orthostatic intolerance. Objective: to explore autonomic profile in a large cohort of adults with hEDS and hypermobility spectrum disorder (hEDS/HSD) with a multimodal approach. In this observational retrospective study, heart rate, blood pressure and baroreflex sensitivity were estimated in 102 hEDS/HSD subjects during deep breathing, Valsalva maneuver, standing up: 30-15 ratio, Head-Up Tilt and sustained handgrip. Abnormal results and head-up tilt test were common and included postural orthostatic tachycardia syndrome (POTS; 48%), orthostatic intolerance (25.5%) and hypotension (3.9%). Baroreflex sensitivity was significantly different in individuals with POTS compared to the others. This study confirms the high rate and heterogeneity of abnormal autonomic regulation in hEDS/HSD, and suggests the baroreflex sensitivity might distinguish comorbid POTS from other profiles in this subgroup of patients. Abnormal autonomic regulation is common in adults with hEDS/HSD and should be regularly assessed for tailoring the management approach.

Objectives A significant proportion of adolescents with chronic musculoskeletal pain (CMP) experience difficulties in physical functioning, mood and social functioning, contributing to diminished quality of life. Generalized joint hypermobility (GJH) is a risk factor for developing CMP with a striking 35-48% of patients with CMP reporting GJH. In case GJH occurs with one or more musculoskeletal manifestations such as chronic pain, trauma, disturbed proprioception and joint instability, it is referred to as generalized hypermobility spectrum disorder (G-HSD). Similar characteristics have been reported in children and adolescents with the hypermobile Ehlers-Danlos Syndrome (hEDS). In the management of CMP, a biopsychosocial approach is recommended as several studies have confirmed the impact of psychosocial factors in the development and maintenance of CMP. The fear-avoidance model (FAM) is a cognitive-behavioural framework that describes the role of pain-related fear as a determinant of CMP-related disability. Content Pubmed was used to identify existing relevant literature focussing on chronic musculoskeletal pain, generalized joint hypermobility, pain-related fear and disability. Relevant articles were cross-referenced to identify articles possibly missed during the primary screening. In this paper the current state of scientific evidence is presented for each individual component of the FAM in hypermobile adolescents with and without CMP. Based on this overview, the FAM is proposed explaining a possible underlying mechanism in the relations between GJH, pain-related fear and disability. Summary and outlook It is assumed that GJH seems to make you more vulnerable for injury and experiencing more frequent musculoskeletal pain. But in addition, a vulnerability for heightened pain-related fear is proposed as an underlying mechanism explaining the relationship between GJH and disability. Further scientific confirmation of this applied FAM is warranted to further unravel the underlying mechanism. In explaining disability in individuals with G-HSD/hEDS, it is important to focus on both the physical components related to joint hypermobility, in tandem with the psychological components such as pain-related fear, catastrophizing thoughts and generalized anxiety.

Ehlers-Danlos syndrome is a rare genetic disorder that presents with a variety of pathologies depending on the disease type. Among them, vascular Ehlers-Danlos syndrome requires extremely careful management as there have been many reports of fatal perinatal complications such as uterine rupture. Although hypermobile Ehlers-Danlos syndrome is less likely to cause fatal complications, symptoms such as arthralgia, hip dislocation, and depression may be seen throughout pregnancy. We report here a case of twin pregnancy in which Ehlers-Danlos syndrome was first suspected at 19 weeks of gestation. Vascular Ehlers-Danlos syndrome could not be ruled out based on family medical history, making it difficult to determine the perinatal management strategy. Prompt genetic testing did however rule out the vascular type and the patient was diagnosed with hypermobile Ehlers-Danlos syndrome from the clinical symptoms, enabling us to manage the pregnancy safely until 34 weeks of gestation., Highlights • In the case of twin pregnancy reported, Ehlers-Danlos syndrome was suspected at 19 weeks of gestation. • Vascular-type Ehlers-Danlos syndrome could not be ruled out based on family medical history. • Twin pregnancies with vascular-type Ehlers-Danlos syndrome have a high maternal risk of mortality. • Prompt genetic testing enabled us to manage the pregnancy safely.

Hypermobile Ehlers-Danlos syndrome (hEDS) is a heritable connective tissue disorder with unknown molecular basis mainly characterized by generalized joint hypermobility, joint instability complications, and minor skin changes. The phenotypic spectrum is broad and includes multiple associated symptoms shared with chronic inflammatory systemic diseases. The stricter criteria defined in the 2017 EDS nosology leave without an identity many individuals with symptomatic joint hypermobility and/or features of hEDS; for these patients, the term Hypermobility Spectrum Disorders (HSD) was introduced. We previously reported that in vitro cultured hEDS and HSD patients' skin fibroblasts show a disarray of several extracellular matrix (ECM) components and dysregulated expression of genes involved in connective tissue homeostasis and inflammatory/pain/immune responses. Herein, we report that hEDS and HSD skin fibroblasts exhibit in vitro a similar myofibroblast-like phenotype characterized by the organization of α-smooth muscle actin cytoskeleton, expression of OB-cadherin/cadherin-11, enhanced migratory capability associated with augmented levels of the ECM-degrading metalloproteinase-9, and altered expression of the inflammation mediators CCN1/CYR61 and CCN2/CTGF. We demonstrate that in hEDS and HSD cells this fibroblast-to-myofibroblast transition is triggered by a signal transduction pathway that involves αvβ3 integrin-ILK complexes, organized in focal adhesions, and the Snail1/Slug transcription factor, thus providing insights into the molecular mechanisms related to the pathophysiology of these protean disorders. The indistinguishable phenotype identified in hEDS and HSD cells resembles an inflammatory-like condition, which correlates well with the systemic phenotype of patients, and suggests that these multisystemic disorders might be part of a phenotypic continuum rather than representing distinct clinical entities.

The 2017 EDS revised nosology indicates that minimal criteria suggestive for classical Ehlers-Danlos syndrome (cEDS) are skin hyperextensibility plus atrophic scarring together with either generalized joint hypermobility (gJHM) and/or at least three minor criteria that include cutaneous features and gJHM complications. Confirmatory molecular testing is obligatory to reach a final diagnosis. Although the large majority of the patients presents with these clinical features, some do not and might remain undiagnosed or misdiagnosed. Here we describe a family with 2 affected members, a 23-year-old proposita and her 51-year-old mother, who presented subtle cutaneous signs, including a variable degree of skin hyperextensibility without extensive widened atrophic scars that apparently better fitted with the overlapping hypermobile EDS. The proposita also presented gastrointestinal symptoms secondary to aberrant mast cells mediators release, making the clinical picture even more puzzling. Both patients were diagnosed by molecular testing that revealed a COL5A1 splice mutation. This report highlights the relevance of molecular analysis in patients presenting rather mild signs of EDS, especially in familial cases, and the importance of clinical expertise to make such a diagnosis.