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In the last decade, growing attention has been placed on joint hypermobility and related disorders. The new nosology for Ehlers-Danlos syndrome (EDS), the best-known and probably the most common of the disorders featuring joint hypermobility, identifies more than 20 different types of EDS, and highlights the need for a single set of criteria to substitute the previous ones for the overlapping EDS hypermobility type and joint hypermobility syndrome. Joint hypermobility is a feature commonly encountered in many other disorders, both genetic and acquired, and this finding is attracting the attention of an increasing number of medical and non-medical disciplines. In this paper, the terminology of joint hypermobility and related disorders is summarized. Different types of joint hypermobility, its secondary musculoskeletal manifestations and a simplified categorization of genetic syndromes featuring joint hypermobility are presented. The concept of a spectrum of pathogenetically related manifestations of joint hypermobility intersecting the categories of pleiotropic syndromes with joint hypermobility is introduced. A group of hypermobility spectrum disorders is proposed as diagnostic labels for patients with symptomatic joint hypermobility but not corresponding to any other syndromes with joint hypermobility. © 2017 Wiley Periodicals, Inc.

The overlap of unexplained gastrointestinal (GI) and somatic symptoms is well established in patients with functional gastrointestinal disorders (FGID). Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder associated with GI and somatic symptoms. We aimed to determine whether there is an association between diagnosis of JHS and FGID and the impact of this association on comorbidities and quality of life (QOL).Prospective case-control study in secondary care GI clinics over 2 years. JHS was assessed by the first author prior to consultation in 641 consecutive new patients. Diagnosis of FGID (cases, n = 336) or organic disorders (controls, n = 305) was established blind to JHS status. JHS prevalence was compared in cases (FGID patients) and controls (organic disorders patients). Extra-intestinal comorbidity and QOL were compared in FGID patients with and without JHS.JHS prevalence was higher in FGID compared to organic GI disorders (39.0% vs 27.5%, ORadj: 1.51, CI: 1.07-2.12, p = 0.02), and particularly associated with functional gastroduodenal disorders (44.1%, ORadj: 2.08, CI: 1.25-3.46, p = 0.005), specifically postprandial distress syndrome (51%, ORadj: 1.99, CI: 1.06-3.76, p = 0.03). FGID patients with JHS had increased chronic pain (23.2% vs 11.9%, p = 0.01), fibromyalgia (10.5% vs 3.1%, p = 0.01), somatization scores (13 vs 10, p0.001), urinary autonomic scores (30.5 vs 20.7, p = 0.03), and worse pain-related QOL scores (45.0 vs 63.5, p = 0.004).JHS is significantly associated with FGID, and this subgroup of patients have increased comorbidity and decreased QOL. Further research is required to understand the pathophysiological basis of this association.

Item does not contain fulltext The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. (c) 2017 Wiley Periodicals, Inc. 01 maart 2017

Background: The model of activity avoidance prompted by fear of increased pain and/or harm dominates understanding and research into activity limitation in chronic pain. Yet, the accounts of people with chronic pain on decisions about activity limitation are rarely heard beyond the confines of fear and avoidance questionnaires. Methods: We used semi-structured interviews to explore the decisions of 11 women attending a pain management clinic with chronically painful Joint Hypermobility Syndrome (JHS). Results: Six themes emerged from Interpretative Phenomenological Analysis: the overall aim of keeping pain to a manageable level, considering whether the planned activity was worth it and, running through all judgements, the influence of pain intensity. The decision was tipped towards avoidance by unpredictability of pain and by high emotional cost and towards going ahead with the activity by the wish to exert control and by low emotional cost. Many accounts described a specifiable cost–benefit analysis of individual decisions, weighing the importance of each activity against its potential aversive consequences, which only in a minority of cases was dominated by fear of pain or injury. Conclusion: Assumptions of fear as the basis of activity avoidance should not be used uncritically in clinical settings. Decisions about activity should explore beyond pain expectancy, incorporating goals, values, and decision processes. Summary points The model of fear of pain or re/injury and associated avoidance, an important insight that has generated effective therapeutic interventions, risks being over-applied and assumed rather than demonstrated. Patients’ own accounts, using qualitative analysis of interview in 11 women with long term chronic pain associated with joint hypermobility, give a more nuanced description of complex decision-making around activity. While a few activities were unquestionably avoided because of such fears, others were undertaken when benefits (according to personal values, such as children’s needs) outweighed costs in pain and distress. We suggest that activity needs to be discussed with patients beyond asking about avoidance and in the context of their lifestyle choices.

Ehlers-Danlos syndrome (EDS)-hypermobility type (HT) is considered to be the most common subtype of EDS and the least severe one; EDS-HT is considered to be identical to the joint hypermobility syndrome and manifests with musculoskeletal complaints, joint instability, and soft tissue overuse injury. Musculoskeletal complaints manifest with joint pain of non-inflammatory origin and/or spinal pain. Joint instability leads to dislocation or subluxation and involves peripheral joints as well as central joints, including the temporomandibular joints, sacroiliac joints, and hip joints. Soft tissue overuse injury may lead to tendonitis and bursitis without joint inflammation in most cases. Ehlers-Danlos syndrome-HT carries a high potential for disability due to recurrent dislocations and subluxations and chronic pain. Throughout the years, extra-articular manifestations have been described, including cardiovascular, autonomic nervous system, gastrointestinal, hematologic, ocular, gynecologic, neurologic, and psychiatric manifestations, emphasizing the multisystemic nature of EDS-HT. Unfortunately, EDS-HT is under-recognized and inadequately managed, leading to neglect of these patients, which may lead to severe disability that almost certainly could have been avoided. In this review article we will describe the known manifestations of the extra-articular systems.

Background Ehlers-Danlos syndrome hypermobility type, also known as Joint Hypermobility Syndrome (EDS-HT/JHS), is the most common hereditary disorder of the connective tissue (HDCT). It is characterized by tissue fragility, joint hypermobility and a wide range of articular and non-articular manifestations, which often appear in infancy. The clinical picture of EDS-HT/JHS is poorly known by the medical community, as is the presence of “ESSENCE” (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) problems in affected children. Aim The present work reviews the clinical and empirical evidence for ESSENCE difficulties in children with EDS-HT/JHS. Method A narrative review of the literature was undertaken following a comprehensive search of scientific online databases and reference lists. This included publications of quantitative and qualitative research. Results Motor abnormality, hyperactivity/hypoactivity, inattention, speech/language, social interaction, behavioral, sleep, feeding and emotional problems are ESSENCE difficulties for which there is some evidence of an association with EDS-HT/JHS. Conclusion Children with EDS-HT/JHS present ESSENCE problems that often coexist and tend to be recognized before the HDCT. Clinicians encountering children with ESSENCE problems should consider the possibility of an underlying HDCT such as EDS-HT/JHS, probably influencing neurodevelopmental attributes in a subgroup of children. Awareness of these interconnected clinical problems might help improve early referral, diagnosis and treatment of EDS-HT/JHS.

Locomotor syndromes are frequent and troublesome in the Marfan syndrome [1, 2]. Close involvement with rheumatologists and orthopaedic surgeons may be indicated to manage painful joint hypermobility and its complications in early to mid-life, and, with increased longevity, degenerative joint disease in later years. Seventy per cent of children experience symptoms of arthralgia, back pain and ligament laxity and injury [1]. The earliest complaints of the child are often knee pain or ankle pain necessitating rest and analgesia. These symptoms, if not appreciated by parents and teachers, may lead to the belief that the child is not trying to participate in family outings or school sporting activities. It is important to allow the child to participate to the extent of his or her ability, but to permit rest, or to terminate the family outing, if the child cannot keep up. Taking a pushchair on family outings makes it a more pleasant activity for all concerned. Allowing the child to act as a referee or a goal keeper or play the least demanding role on the team at school is helpful. Weak ankles and knees, combined with poor eyesight may make the children appear clumsy in sporting activities, and they soon lose interest. It is important to wear sports shoes with ankle support, and even arch supports and heel cups, to render the gait more controlled. Ankle and knee supports may be worn to stabilise these joints, which are prone to recurrent sprains, and in some cases patellar dislocation. In severe cases, surgical fusion of the ankle, or shortening of the patellar ligaments may be helpful. Patients should be taught to gently reduce recurrent dislocations of patellae, fingers and toes. These joints gain stability with passing years. Wrist or finger splints may help to stabilise the loose wrist, thumb or fingers, and render writing neater. If the hand tires, especially during examinations, extra time should be given. Using fat pens or pencils, which may be built up, makes the handwriting more legible. For older children, the use of a laptop computer, or even a tape recorder to record lessons, may avoid the need for handwritten notes.

Postural tachycardia syndrome (PoTS) is a poorly understood but important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. PoTS is distinct from the syndromes of autonomic failure usually associated with orthostatic hypotension, such as pure autonomic failure and multiple system atrophy. Individuals affected by PoTS are mainly young (aged between 15 years and 40 years) and predominantly female. The symptoms--palpitations, dizziness and occasionally syncope--mainly occur when the patient is standing upright, and are often relieved by sitting or lying flat. Common stimuli in daily life, such as modest exertion, food ingestion and heat, are now recognized to be capable of exacerbating the symptoms. Onset of the syndrome can be linked to infection, trauma, surgery or stress. PoTS can be associated with various other disorders; in particular, joint hypermobility syndrome (also known as Ehlers-Danlos syndrome hypermobility type, formerly termed Ehlers-Danlos syndrome type III). This Review describes the characteristics and neuroepidemiology of PoTS, and outlines possible pathophysiological mechanisms of this syndrome, as well as current and investigational treatments.

Objective.The stress/strain curve derived from stretching skin is not linear, but follows a J-shaped curve. An initial generous yield is followed by a steep linear phase where considerable additional force is required to achieve modest increases in deformation. The former represents the taking up of slack resulting from the alignment of dermal collagen bundles in the line of force, while the gradient of the latter represents Young’s modulus for skin. Skin hyperextensibility in Ehlers-Danlos syndrome (EDS) is limited to the initial phase of taking up slack. Skin hyperextensibility and joint hypermobility (JHM) form part of the Revised 1998 Brighton diagnostic criteria for the benign joint hypermobility syndrome (BJHS), considered by many to be akin to EDS-hypermobility type. JHM may be screened for using the Beighton Score or a 5-point questionnaire. Our aim was to validate a novel method of measuring skin extensibility based on these observations in addition to revalidating the 5-point questionnaire.Methods.250 volunteers (131 female), median age 39 years (range 18–89 yrs), without BJHS, had their joint mobility evaluated using the Beighton Score, compared to the 5-point questionnaire. A Beighton score ≥ 4/9 was considered to represent JHM. Skin extensibility was determined by placing 2 dots on the dorsum of the right hand between the second and third metacarpals, approximately 10 mm apart, and was measured using an electronic caliper. Perpendicular to the metacarpals, a force was applied until the skin was fully taut and the increment was measured. Skin-fold thickness was measured using a Harpenden caliper. A corrected skin extensibility score (CSES) was calculated by dividing the percentage increment by skin thickness. Interobserver variability was measured in a further 50 healthy volunteers.Results.The prevalence of JHM was 17.6%. Revalidation of the 5-point questionnaire returned a sensitivity of 0.85 and specificity of 0.85. The mean CSES was 23.84%/mm in the hypermobile group versus 13.55%/mm in the normal mobility group (p < 0.0001). CSES sensitivity was 0.72, specificity 0.75. The κ value for interobserver variability was 0.83.Conclusion.The CSES is a useful and reproducible measure of skin extensibility in health. Further work is warranted to validate this test in patients with BJHS.

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Joint hypermobility syndrome (JHS) is common in patients presenting to rheumatologists and can cause a range of symptoms leading to physical and psychological distress. Chronic musculoskeletal pain in patients with JHS often responds poorly to analgesics, and a pain management approach may be helpful. Since patients with JHS often have beliefs and experiences different to those of other chronic pain patients, they could fare better in JHS-specific programmes. Here, we report on the outcomes of patients in a JHS cognitive behavioural pain management programme. Patients fulfilling the Brighton criteria for JHS, who had suffered pain for at least 3 months, were assessed by a psychologist and physiotherapist for suitability for this programme. Those accepted took part in a programme of 8 days spread over 6 weeks, delivered by a multidisciplinary team and incorporating a cognitive behavioural approach. Outcomes were assessed at baseline, 1- and 5-month post-programme using validated outcome measures. Outcome measures at baseline and 1-month were available for 87 patients (96 % female, mean age 35 years). There were significant improvements in self-efficacy, pain catastrophising, depression, anxiety, frustration, impact of pain and average pain intensity (all P

The HDCTs constitute a heterogeneous group of rare genetically determined diseases, the best known of which are Ehlers-Danlos and Marfan syndromes and osteogenesis imperfecta. Hypermobility is a feature common to them all, but it is also a feature that is highly prevalent in the population at large. Symptomatic hypermobile subjects (whose symptoms are attributable to their hypermobility) are said to be suffering from the benign joint hypermobility syndrome, which has many features that overlap with the HDCTs. It is not yet known whether there is a variety of hypermobility (symptomatic or otherwise) that is not part of a connective tissue disorder.

The genetically determined rheumatological connective tissue disorders constitute a group of phenotypically related inherited conditions caused by aberrations in genes encoding the fibrous connective tissue matrix proteins (collagens, elastins, fibrillins and tenascins). In several (but not all) of these conditions, the precise genetic cause has been identified. A common clinical feature is joint hypermobility. The frequently encountered, yet largely neglected, joint hypermobility syndrome is a source of much unrecognized morbidity and unnecessary suffering in the community.

Joint hypermobility syndrome is a common clinical entity which is much misunderstood, overlooked, misdiagnosed and mistreated. It was first described in the 1960s as a purely musculoskeletal condition due to joint laxity and hypermobility occurring in otherwise healthy individuals. Some four decades later it is now perceived to be a multi-systemic heritable disorder of connective tissue with manifestations occurring far beyond the confines of the locomotor system and with ramifications potentially affecting most, if not all, of the bodily systems in one way or another. Most authorities in the field find it clinically indistinguishable from the Ehlers-Danlos syndrome--hypermobility type (formerly, EDS type III). In >50% of patients the diagnosis is delayed for ≥10 years. Failure to diagnose and treat the condition correctly results in needless pain and suffering and in many patients to a progressive decline in their quality of life and in some to a loss of independence.

Although perceived as a rare condition, joint hypermobility syndrome is common. Its prevalence in rheumatology clinics is extremely high. Early estimates suggest that it may be the most common of all rheumatologic conditions. The problem lies in the general lack of awareness of the syndrome, its means of recognition, and the resultant failure to diagnose it correctly when present. It is a worldwide problem. This article provides an overview of hypermobility and hypermobility syndrome, stressing its multisystemic nature and the negative impact that it may have on quality of life, with particular reference to gastrointestinal involvement.

Arachnodactyly literally means spidery fingers, and describes the long, slender fingers typical of patients with Marfan syndrome (MFS). Many clinicians regard arachnodactyly as pathognomonic of MFS; however, this view is misleading as arachnodactyly is a key element of the marfanoid habitus, which is present in several heritable disorders of connective tissue (HDCTs). Other features of the marfanoid habitus include long hands and feet, increased skin stretch, joint hypermobility and characteristic changes in the physiology of the pectum. Here, we focus on the differential diagnosis of diseases with features of the marfanoid habitus. Ectopia lentis (lens dislocation) and aortic root dilation or dissection are cardinal features of MFS. Distinguishing MFS from other HCDTs has important implications for treatment, as cardiovascular and ocular complications commonly seen in patients with MFS are not seen in all HDCTs. Joint hypermobility syndrome and Ehlers-Danlos syndrome are also HDCTs, neither of which is associated with ectopia lentis or aortic changes. Some of the rarer forms of Ehlers-Danlos syndrome are associated with severe vascular, dental and skin pathologies. This Review serves as a guide for correctly diagnosing members of the HDCT family.

The objective of the study was to ascertain the occurrence and inter-relationships of locomotor symptoms, joint hypermobility and skin involvement in patients with the Marfan syndrome. A single clinical evaluation, using a standardized protocol, of randomly selected out-patients was made. Joint hypermobility was measured by two scales in wide clinical use (Beighton and Contompasis), skin hyperextensibility was assessed on the dorsum of the hand, and skin thickness and light transmissibility was measured at the same site with a modified Harpenden caliper. The setting was an out-patient medical genetics clinic at an urban teaching hospital in Baltimore, Maryland, USA. The subjects comprised 27 children and 48 adults who met strict diagnostic criteria for the Marfan syndrome. In patients less than 18 yr old, 70% had experienced at least one locomotor syndrome, and 40% had had multiple symptoms, of which arthralgia, myalgia and ligamentous injury were the most frequent. Symptoms were absent in children younger than 5 yr. Thereafter, the number of symptoms increased with age. Considerable joint hyperextensibility (> 3/9 of Beighton's criteria) was present in 85%. While one-third had received orthopaedic attention, there had been little if any rheumatological input. In adult patients, locomotor symptoms had occurred in 96%, with 88% having experienced more than one complaint. Spinal pain, arthralgia, ligament injury and fracture were the most common. Most (81%) of the adults had some (> 1/9), and 56% had considerable (> 2/9) evidence of joint hypermobility. Only 20% had received specialist attention for their locomotor symptoms. Skin changes are documented in the Marfan syndrome for the first time in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Joint hypermobility is a common connective tissue variant. Surprisingly, people with this disorder are especially vulnerable to anxiety. Recent imaging studies suggest that non-anxious individuals with hypermobility express structural and functional differences in emotional brain regions. Autonomic dysregulation, typically postural tachycardia, is often found. Our aim was to test the hypothesis that joint hypermobility increases the expression of anxiety through aberrant central autonomic control. Methods The study had a 2×2 factorial design (presence or absence of hypermobility×presence or absence of generalised anxiety disorder). Adults with generalised anxiety disorder and healthy controls were prospectively recruited so that half of each group had hypermobility. Autonomic testing was done before measurement by functional MRI of brain responses to emotional stimuli. Between-group analyses tested for differences in autonomic function and patterns of brain activation. Presence of generalised anxiety disorder was assessed with DSM-IV criteria (MINI, MINI International Neuropsychiatric Interview). Anxiety was quantified with the Beck Anxiety Inventory. All neuroimaging findings are presented at a significance threshold of p(FWE corrected) Findings 70 adults were recruited (32 with generalised anxiety disorder, of whom 16 had hypermobility; 38 controls of whom 19 had hypermobility). An increase in sympathetic reactivity (proportional change in heart rate on active standing) was observed in individuals with hypermobility (n=35) versus those without hypermobility (n=35) (mean change from baseline 22·4% [SE 2·7] vs 14·2 [2·1], p=0·024) and in those with generalised anxiety disorder (n=32) versus those without anxiety (n=38) (24·0 [2·9] vs 13·9 [1·9], p=0·005), correlating with hypermobility ( r =0·34, p=0·024) and anxiety scores ( r =0·38, p=0·004). There was an interaction between the effects of hypermobility and anxiety on sympathetic reactivity (p=0·001). Within the brain, individuals with hypermobility showed increased reactivity to emotional stimuli within brain areas implicated in emotional processing and autonomic control, notably amygdala (p[FWE corrected] Interpretation This study shows that joint hypermobility is associated with the expression of anxiety through autonomic hyper-reactivity linked to aberrant engagement of the amygdala and insula. This study is the first, to our knowledge, to provide a mechanistic understanding of the association between joint hypermobility and anxiety; the findings will enhance recognition across medical disciplines of extra-articular features and vulnerabilities of joint hypermobility, offering possibilities for optimum personalised medicine. Funding Medical Research Council.

The ability of joints to undergo repeated and rapid movements is attributable to the unique mechanical properties of the extracellular matrix (ECM) of the joint capsule and surrounding ligaments and tendons. A delicate balance exists between ‘stiffness’ and ‘elasticity’ of these tissues. Stiffness comes from very long collagen fibrils that are arranged in elaborate architectures such as parallel bundles in tendon (Fig. 3.1), orthogonal lattices in the cornea and basket-weave in skin, depending on the mechanical requirements of the tissues in which they occur. Elasticity originates from the crimping of collagen fibrils and from elastic fibres in the ECM (Fig. 3.2). These elastic fibres have a unique arrangement of macromolecules that permits extension and contraction at a molecular level. An understanding of the molecular and structural basis of joint hypermobility requires a detailed knowledge of the structure, function and organisation of the collagenous and elastic polymer systems that comprise the ECM.

The first clinical description of articular hypermobility is attributed to Hippocrates, who, in the fourth century B.C., described the Scythians, a race of people inhabiting the region that now forms the Ukraine and Czechoslovakia, as having humidity, flabbiness and atony such that they were unable to use their weapons. Their main problem in warfare was that hyperlaxity of the elbow and shoulder joints prevented them from drawing their bows effectively.

Individuals endowed with hypermobility may excel in certain artistic occupations. The professional activities of ballet dancers, contortionists, musicians and sportsmen are all influenced by their range of joint movements. The wider implications of this situation are reviewed in this chapter.

A common clinical error is to confuse these two terms, which are not synonymous. Hypermobility is defined as an excessive range of joint motion, taking into consideration the age, gender and ethnic origin in otherwise healthy subjects, being greater in males than females, in younger people compared with older people and in those of Asian or African origin compared to those who are Caucasian. It is characterised by an inherent increase in laxity and fragility of the connective tissues. Hypermobility is a direct consequence of ligamentous laxity, which, itself, is an expression of a genetically determined aberration of one or more of the connective tissue fibrous protein genes such as those encoding for collagen(s), fibrillin(s) or tenascin(s)

Adequate methods for measuring the range of movement at joints are essential for the definition of criteria used in the study of clinical problems associated with joint hypermobility. Scoring systems for hypermobility that survey a large number of joints in simple fashion are ideal for epidemiological studies in large populations. Latterly, investigators have devised sophisticated mechanical devices for the precise quantification of movement at a single joint. The greater precision afforded may be ideal for serial assessments in the same patient but this greater precision is of limited use in epidemiological work if the joint fails to mirror the status of laxity at other joints in the body. Moreover, a joint may display acquired hyperlaxity in compensation for a reduced range of movement at adjacent joints, for example in the vertebral column.

First published online: April 10, 2011

We carried out a segregation analysis comparing the inheritance of collagen gene markers and joint hypermobility syndrome in two extended families. Our results exclude the genes encoding type III (COL3A1), type V alpha 2 chain (COL5A2) and type VI alpha 3 chain (COL6A3) unambiguously in both families. The simultaneous exclusion of both the type 1 alpha 1 and alpha 2 chain genes in the same family was not possible: COL1A1, but not COL1A2 was excluded in one and COL1A2, but not COL1A1 was excluded in the second. There was no suggestion of strong linkage to either of these loci. These data do not support the hypothesis that JHS in these families is caused by mutations in these collagen genes.

Joint hypermobility syndrome (JHS) was initially defined as the occurrence of musculoskeletal symptoms in the presence of joint laxity and hypermobility in otherwise healthy individuals. It is now perceived as a commonly overlooked, underdiagnosed, multifaceted, and multisystemic heritable disorder of connective tissue (HDCT), which shares many of the phenotypic features of other HDCTs such as Marfan syndrome and Ehlers-Danlos syndrome. Whereas the additional flexibility can confer benefits in terms of mobility and agility, adverse effects of tissue laxity and fragility can give rise to clinical consequences that resonate far beyond the confines of the musculoskeletal system. There is hardly a clinical specialty to be found that is not touched in one way or another by JHS. Over the past decade, it has become evident that of all the complications that may arise in JHS, chronic pain is arguably the most menacing and difficult to treat.

The Lack of Clinical Distinction Between the Hypermobility Type of Ehlers–Danlos Syndrome and the Joint Hypermobility Syndrome (a.k.a. Hypermobility Syndrome) Brad T. Tinkle,* Howard A. Bird, Rodney Grahame, Mark Lavallee, Howard P. Levy, and David Sillence Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio University of Leeds, West Yorkshire, United Kingdom University College Hospital, London, United Kingdom Memorial Sports Medicine Institute, South Bend, Indiana Johns Hopkins University, Baltimore, Maryland Connective Tissue Dysplasia Management Service, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia

BACKGROUND Unexplained gastrointestinal (GI) symptoms and joint hypermobility (JHM) are common in the general population, the latter described as benign joint hypermobility syndrome (BJHS) when associated with musculo-skeletal symptoms. Despite overlapping clinical features, the prevalence of JHM or BJHS in patients with functional gastrointestinal disorders has not been examined. METHODS The incidence of JHM was evaluated in 129 new unselected tertiary referrals (97 female, age range 16-78 years) to a neurogastroenterology clinic using a validated 5-point questionnaire. A rheumatologist further evaluated 25 patients with JHM to determine the presence of BJHS. Groups with or without JHM were compared for presentation, symptoms and outcomes of relevant functional GI tests. KEY RESULTS Sixty-three (49%) patients had evidence of generalized JHM. An unknown aetiology for GI symptoms was significantly more frequent in patients with JHM than in those without (P < 0.0001). The rheumatologist confirmed the clinical impression of JHM in 23 of 25 patients, 17 (68%) of whom were diagnosed with BJHS. Patients with co-existent BJHS and GI symptoms experienced abdominal pain (81%), bloating (57%), nausea (57%), reflux symptoms (48%), vomiting (43%), constipation (38%) and diarrhoea (14%). Twelve of 17 patients presenting with upper GI symptoms had delayed gastric emptying. One case is described in detail. CONCLUSIONS & INFERENCES In a preliminary retrospective study, we have found a high incidence of JHM in patients referred to tertiary neurogastroenterology care with unexplained GI symptoms and in a proportion of these a diagnosis of BJHS is made. Symptoms and functional tests suggest GI dysmotility in a number of these patients. The possibility that a proportion of patients with unexplained GI symptoms and JHM may share a common pathophysiological disorder of connective tissue warrants further investigation.

Rheumatologists have long considered that joint hypermobility is inherited. The familial aggregation is striking and the pattern of inheritance strongly points to an autosomal dominant mode. The first comprehensive description of symptomatic joint hypermobility in the rheumatological literature is attributed to Kirk, Ansell and Bywaters in 1967 [1]. They coined the term ‘hypermobility syndrome’ (HMS). Later, the recognition of the relatively benign prognosis of the HMS in terms of life-threatening complications led to the use of the term ‘benign joint hypermobility syndrome’ (BJHS) or latterly, the ‘joint hypermobility syndrome’ (JHS). Early workers believed that joint hypermobility merely represented the upper end of a Gaussian distribution of the range of normal physiological movement [2]. Later it became apparent that connective tissues other than joints, such as skin, bone and eye, participated in the connective tissue fragility seen in JHS. These clinical signs of connective tissue fragility are usually most prominent in the different forms of heritable disorders of connective tissue (HDCTs) such as Marfan syndrome (MFS), osteogenesis imperfecta (OI) and the Ehlers–Danlos syndromes (EDS). Marfan syndrome is an autosomal dominant disorder characterized by aortic dilatation, ectopia lentis, marfanoid habitus and mild to moderate joint hypermobility [3]. Osteogenesis imperfecta, another autosomal dominant HDCT, is mainly characterized by varying degrees of bone fragility, blue sclerae, short stature and mild joint hypermobility. The EDS comprise a clinically and genetically heterogeneous group of connective tissue diseases of which the principal clinical features are joint hypermobility, skin hyperextensibility, delayed wound healing with atrophic scarring and generalized connective tissue fragility [4]. There exists, however, a phenotypic overlap between these forms of HDCT. The marfanoid habitus (Table 1) for instance was once considered to be pathognomonic for MFS. This notion is no longer tenable. Marfanoid habitus can be seen in a host of HDCTs, as illustrated in Table 2. Similarly, the blue sclerae, once thought to occur only in OI are now considered to have a wider relevance as a non-specific pointer to collagen deficiency. Skin hyperextensibility (and associated bruising, delayed healing and atrophic scarring) originally identified exclusively with EDS, is also recognized in MFS [3]. Although brittle bones were initially considered to feature only in OI, a reduction in bone mineral density detected by Dual energy x-ray absorptiometry (DEXA) scanning has been demonstrated in both EDS [5] and MFS [6]. With recognition of the presence of mild fragility of connective tissues other than the joints in patients with JHS, it became evident that JHS is itself an under-recognized form of an HDCT. Patients with JHS can present mild expression of marfanoid habitus (Table 2), osteoporosis, blue sclerae, skin hyperextensibility, atrophic scarring or easy bruising [7, 8] (Table 3). Since these features can also be present in the most common form of EDS, the hypermobility type (or former type III), it seems increasingly likely that JHS is, if not identical, indistinguishable from the hypermobility type of EDS [9].

When taking biopsies to assess skin strength in Ehlers–Danlos syndrome type III (EDS–III), a Danish group noticed that the patients experienced much pain despite conventional local anaesthesia.1 When asked, all these patients reported previous experience of partial or complete failure of local anaesthesia in dental or obstetric procedures—for which reason some had been dismissed as hysterics. Pursuing this finding, Arendt-Nielsen et al.2 compared the effects of local anaesthesia in 8 patients with EDS–III and 8 controls. Although the patients did gain analgesia from intradermal lidocaine the duration of effect was much shorter than in controls. EDS–III (now known as EDS–hypermobility type) is regarded by many authorities as identical to joint hypermobility syndrome (JHS).3,4 We wish to draw attention to the possibility of resistance to local anaesthesia in individuals with this common and under-diagnosed condition. Box 2 Five-part questionnaire for identifying hypermobility (Ref. 7) Answers in the affirmative to 2 or more questions suggest hypermobility with sensitivity 80–85% and specificity 80–90% Can you now (or could you ever) place your hands flat on the floor without bending your knees? Can you now (or could you ever) bend your thumb to touch your forearm? As a child did you amuse your friends by contorting your body into strange shapes OR could you do the splits? As a child or teenager did your shoulder or kneecap dislocate on more than one occasion? Do you consider yourself double-jointed? Box 3 Brighton criteria for joint hypermobility syndrome (JHS) (Ref. 8) JHS is diagnosed in the presence of two major criteria, or one major and two minor criteria, or four minor criteria. Two minor criteria will suffice where there is an unequivocally affected first-degree relative. Major Beighton score of 4 out of 9, or more (either currently or historically) Arthralgia for longer than 3 months in four or more joints Minor A Beighton score of 1, 2 or 3 out of 9 (0, 1, 2 or 3 if aged 50+) Arthralgia in 1–3 joints, or back pain or spondylosis, spondylolysis/spondylolisthesis Dislocation in more than one joint, or in one joint on more than one occasion Three or more soft tissue lesions (e.g. epicondylitis, tenosynovitis or bursitis) Marfanoid habitus (tall, slim, arm span >height, arachnodactyly) Skin striae, hyperextensibility, thin skin or abnormal scarring Eye signs: drooping eyelids, or myopia, or anti-mongoloid slant Varicose veins, or hernia, or uterine/rectal prolapse Many normal people have hypermobile joints and medical diagnosis of the medical syndrome requires symptoms—which can include chronic pain, impairment of proprioception, and temporomandibular joint dysfunction (a manifestation of which dentists may be unaware).5 JHS is overrepresented in general rheumatology clinic populations and in our experience (RG and AJH)6 many of these patients report failure of local anaesthetics. This matter was addressed briefly in a paper published in 2003.7 A questionnaire was completed by 172 female Caucasian JHS patients, 53 non-hypermobile age-matched controls, and 28 individuals who showed evidence of hypermobility with insufficient features to qualify for JHS (HM-sine-JHS) as defined by the Brighton criteria.8 We asked ‘If you have ever had a local anaesthetic injection (dentist/minor surgery/epidural), did you think that it was as effective as it should have been?’. 58% of JHS patients, 21% of controls and 14% of the HM-sine-JHS group answered in the negative. For JHS versus controls the odds ratio was a highly significant 2.85. Although the question was simplistic, non-exploratory, and reliant on recall and selfperception, the difference between JHS and controls was striking. Neither group had knowledge of any study hypothesis. At the time there was nothing of this nature documented in patient information sheets or published research. We suspect that in many people JHS goes unrecognized. So, how can a busy clinician, mindful of possible resistance to local anaesthesia, make the diagnosis? There are two easy methods for identifying hypermobility—carry out a Beighton score9 (Box 1); or ask the patient to answer a five-part screening questionnaire7 (Box 2). The phenotype is shown in Box 3. Box 1 The nine-point Beighton hypermobility score (Ref. 9) One point may be gained for each side for manoeuvres 1–4 so that the hypermobility score will have a maximum of nine points if all are positive. A score of ≥4/9 indicates widespread ... Although the pathophysiology of this phenomenon remains unresolved, an important clue that a patient is at risk of local anaesthetic failure might be in front of our eyes.

Objective To estimate the genetic influence on joint hypermobility in an unselected population using a classic twin study design. Methods A self-report questionnaire on joint hypermobility as well as data on age, height, weight, estrogen replacement therapy, and menopause status were obtained from 483 monozygotic (MZ) and 472 dizygotic (DZ) unselected female twin pairs ages 21–81 years who were registered with the St Thomas' Adult Twin Registry in the UK. Results The overall prevalence of hypermobility was 19.5% in MZ twins and 22.1% in DZ twins. The prevalence of hypermobile joints declined with age, falling from 34% in subjects ages 20–30 years to 18.4% in those ages 60 years or older. Significantly greater concordance for joint hypermobility was observed in the MZ twins when compared with the DZ twins (60% versus 36%), consistent with a genetic influence. In variance components analysis, the age- and body mass index–adjusted heritability of joint hypermobility was estimated to be 70% (95% confidence interval 57–89%). Conclusion Genetic factors have a substantial contribution to joint hypermobility in the adult female population.

Purpose Extraarticular manifestations of the joint hypermobility syndrome may include the peripheral nervous system. The purpose of this study was to investigate autonomic function in patients with this syndrome. Methods Forty-eight patients with the joint hypermobility syndrome who fulfilled the 1998 Brighton criteria and 30 healthy control subjects answered a clinical questionnaire designed to evaluate the frequency of complaints related to the autonomic nervous system. Next, 27 patients and 21 controls underwent autonomic evaluation: orthostatic testing, cardiovascular vagal and sympathetic functions, catecholamine levels, and adrenoreceptor responsiveness. Results Symptoms related to the autonomic nervous system, such as syncope and presyncope, palpitations, chest discomfort, fatigue, and heat intolerance, were significantly more common among patients. Orthostatic hypotension, postural orthostatic tachycardia syndrome, and uncategorized orthostatic intolerance were found in 78% (21/27) of patients compared with in 10% (2/21) of controls. Patients with the syndrome had a greater mean (± SD) drop in systolic blood pressure during hyperventilation than did controls (–11 ± 7 mm Hg vs. –5 ± 5 mm Hg, P = 0.02) and a greater increase in systolic blood pressure after a cold pressor test (19 ± 10 mm Hg vs. 11 ± 13 mm Hg, P = 0.06). Patients with the syndrome also had evidence of α-adrenergic (as assessed by administration of phenylephrine) and β-adrenergic hyperresponsiveness (as assessed by administration of isoproterenol). Conclusion The autonomic nervous system–related symptoms of the patients have a pathophysiological basis, which suggests that dysautonomia is an extraarticular manifestation in the joint hypermobility syndrome.

Background & Aims The Joint Hypermobility Syndrome (JHS) is a common connective tissue disorder characterized by joint hyperflexibility, dysautonomia, and chronic pain. Gastrointestinal (GI) symptoms are reported in JHS patients attending rheumatology clinics, but the prevalence and symptom pattern of previously undiagnosed JHS in GI clinics are unknown. Methods By using validated questionnaires, a prospective cross-sectional study in secondary care GI clinics estimated the prevalence of JHS in new consecutively referred patients, compared GI symptoms in patients with and without JHS, and by using multiple regression determined whether the burden of GI symptoms in JHS patients was dependent on chronic pain, autonomic, psychological, and medication related factors. A positive control group consisted of JHS patients referred from rheumatology clinics with GI symptoms (JHS-Rh). Results From 552 patients recruited, 180 (33%) had JHS (JHS-G) and 372 did not (non-JHS-G). Forty-four JHS-Rh patients were included. JHS-G patients were more likely to be younger, female with poorer quality of life ( P = .02) than non-JHS-G patients. After age and sex matching, heartburn (odds ratio [OR], 1.66; confidence interval [CI], 1.1–2.5; P = .01), water brash (OR, 2.02; CI, 1.3–3.1; P = .001), and postprandial fullness (OR, 1.74; CI, 1.2–2.6; P = .006) were more common in JHS-G vs non-JHS-G. Many upper and lower GI symptoms increased with increasing severity of JHS phenotype. Upper GI symptoms were dependent on autonomic and chronic pain factors. Conclusions JHS is common in GI clinics, with increased burden of upper GI and extraintestinal symptoms and poorer quality of life. Recognition of JHS will facilitate multidisciplinary management of GI and extra-GI manifestations.

Introduction The Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder with a prevalence of 20%. It is characterised by joint hypermobility,chronic pain, fibromyalgia (FM) and dysautonomia. Gastrointestinal (GI) symptoms e.g., dyspepsia, reflux, bloating and constipation are present in up to 80% of affected individuals. Small studies suggest that FGID are common in these patients yet no controlled studies have systematically investigated if JHS is associated with particular GI diagnoses nor explored the effect of JHS on non-GI symptom presentation and quality of life (QOL). Methods Using a nested case-control double-blind study in secondary care GI clinics, consecutive new referrals (without prior GI diagnosis), aged 18–70, completed validated questionnaires for GI, somatic, psychological and autonomic symptoms and QOL, and were assessed for JHS and FM. They then consulted a gastroenterologist, underwent investigations and received a GI diagnosis. ROME III criteria were used to categorise FGID. A control group of patients, aged 18–70, who were referred to secondary care for non-GI related problems, were similarly assessed. The prevalence of JHS in various GI diagnoses and in controls,adjusted for age and gender,was compared. Non-GI characteristics and QOL was compared in JHS and non-JHS patients. Results 688 GI patients [254 organic: (55% F, 43y); 341 FGID: (65% F, 40y); 53 reflux: (40% F, 46y)] and 93 non-GI controls (67% F, 43y) were included. JHS prevalence was higher in FGID (38%) and reflux (40%) compared to organic disorders (26%) and controls (26%) (p = 0.003). JHS was significantly associated with FGID (ORadj: 1.7, CI:1.02–2.88), specifically postprandial distress syndrome (ORadj 2.2, CI: 1.2–2.2), and with reflux disorders (ORadj 2.2, CI: 1.1–4.7), but not with organic disorders (ORadj: 1.0, CI:0.6–1.8). FGID patients with JHS had significantly more FM (12.6 vs. 4.9%, p = 0.02), chronic pain (23.2 vs. 11.7%, p = 0.01), somatisation scores (13 vs. 10, p Conclusion JHS is associated with functional dyspepsia, and non-erosive reflux disease, and with FM, chronic pain, somatisation and anxiety. Clinical assessment for JHS in GI clinics is indicated in those with a combination of functional upper GI symptoms and extra-intestinal symptoms as this may help earlier identification of a more ‘challenging’ group of patients with multiple somatic symptoms and worse QOL. These may benefit from early multidisciplinary approach involving rheumatologists and pain specialists. Disclosure of Interest None Declared.

In an early paper, Sutro (1947) drew attention to the biomechanical aspects of hypermobility. In a study of recurrent effusions in the knees and ankles of American army recruits, he noted an increased range of both active and passive movement in the affected joints. He argued in favour of an “over-length” of certain articular, capsular and ligamentous tissues, and suggested that there might be disproportion in the relative rate of growth of the bones and their attached ligaments.

The following case histories have been drawn from the records of patients who have attended the Guy’s Hospital Hypermobility Clinic over the past two decades, many of whom have been observed over several years. A striking finding has been the number and variegated pattern of locomotor disorders suffered by individual patients. Many of the disorders encountered were amenable to treatment, and serious disablement was seen in only a few individuals. In each instance the Beighton et al. (1973) mobility scale was used.

The majority of persons with lax ligaments and loose joints suffer no articular problems. For example, rheumatic complaints were no more prevalent amongst a group of 31 healthy hypermobile blood donors (average age 28 years) than in age- and sex-matched controls (Jessee et al. 1980). For most hypermobile subjects it is a positive attribute which enables enhanced participation in a wide variety of physical activities (see Chap. 9). However, not all are so fortunate, and some experience locomotor and other problems as a direct result of their laxity. When symptoms result, the term hypermobility syndrome (HMS) is applied (Kirk et al. 1967). It must be emphasised that this designation is non-specific and in this context it does not denote any precise disease entity. Within an unselected group of 100 HMS patients, Finsterbush and Pogrund (1980) delineated three patterns of musculoskeletal complaint: (1) mild complaints of long duration, (2) acute episodes at various sites and (3) a combination of these.

Cardiac abnormalities such as mitral valve prolapse (MVP) are reported to be common features of the Ehlers Danlos syndrome (EDS), and it has been suggested that the majority of patients with type IV EDS will have cardiac involvement and vascular aneurysms. However, the evidence for valve lesions is inconsistent and often based on early clinical studies using mainly M-mode echo. We studied 33 patients (six male, 27 female; median age 35 yr) with EDS (30 type I, II or III, three type IV) and 30 age- and sex-matched controls. The study assessed skin stretch and joint hypermobility using Beighton and Contompasis scores. Echocardiographic examination included standard two-dimensional views from the parasternal and apical windows, and measurement of the aorta at four sites (annulus, sinotubular junction, arch and abdominal aorta). Echocardiographic abnormalities were found in four patients (12.1%) (one atrial septal aneurysm, one tricuspid prolapse, two MVP) and two controls (6.7%). MVP was found in 6.1% of EDS patients and 7% of controls. Seven patients had previously been diagnosed as having MVP; only two were shown to have true MVP using current criteria. None of those with type IV EDS had any echocardiographic abnormality. No patients with EDS had mean aortic dimensions outside the normal range at any of the points tested. Cardiac symptoms were more frequent amongst the patients than controls (atypical chest pain 48%, P = 0.0001; palpitation 39%, P = 0.001; exertional dyspnoea 30%). A wide range of rheumatological complaints were reported (current arthralgia 75%; recent back pain 72%, P = 0.005; recurrent dislocation 72%). Contrary to earlier published observations, we have not found an increased incidence of cardiac abnormalities in EDS. This syndrome may be relatively more benign, from the cardiac point of view, than was previously thought.

Introduction Functional Gastrointestinal Disorders (FGID) are common, but their cause is unknown. Joint hypermobility syndrome (JHS) is a common non-inflammatory connective tissue disorder characterised by joint hyperflexibility. It is associated with gastrointestinal (GI) symptoms (1), in particular unexplained symptoms (2). The association between JHS and FGID has never been studied. Methods A nested case control study in patients aged 18–70 attending secondary care was performed. 694 consecutive new referrals to GI clinics were assessed for JHS using the Brighton criteria, prior to their outpatient consultation. Subsequent investigation by their gastroenterologist led to a diagnosis that was functional, organic or gastrooesophageal reflux (GOR); the latter were excluded due to the mixed aetiology of reflux. The control group consisted of 92 patients referred to secondary care for non-GI symptoms-those with diabetes, pregnancy, neuromuscular disorders or inflammatory arthritis were excluded. Controls were similarly assessed for JHS. JHS prevalence was compared in patients with FGID, organic GI disorders, and controls. Results Of the 694 GI patients, 26 had GOR and 52 had not received a diagnosis–these were excluded. Thus 616 GI patients were included in the study: 363 had FGID, 253 had organic disorders. There were no significant age or gender differences between FGID and controls (age: 40.3 ± 0.69 vs 42.7 ± 1.5; 64% vs 67% females). Compared to FGID patients, organic patients were older (43.9 ± 0.92 vs 40.3 ± 0.69, p:0.002) and less likely to be female (54% vs 64%, p:0.008).The prevalence of JHS in FGID patients in secondary care was 40.5%. This was significantly higher than in organic GI patients (26.9%, p:0.000) and in controls (25%, p:0.006). Even after adjusting for age and gender differences, JHS was significantly associated with FGID (p:0.005). Conclusion This is the first study that demonstrates a strong association between JHS and FGID, as compared to both organic GI and non-GI conditions. This suggests a potential connective tissue aetiology for 40% of FGID patients in secondary care. Furthermore, the high prevalence of JHS in FGID suggests that this common diagnosis is often overlooked. Our results have implications for future FGID research and efforts must now be focused to determine the mechanism of symptoms and identification of appropriate treatments for this subgroup of patients. Disclosure of Interest None Declared References Castori, M., et al. , Am J Med Genet A, 2010. 152A (3): p. 556–64. Zarate, N., et al. , Neurogastroenterol Motil, 2010. 22 (3):252-e78.

Introduction The Joint Hypermobility Syndrome (JHS) is a hereditary connective tissue disorder, characterised by hyperflexibility of the skin and joints and musculoskeletal symptoms. A high prevalence of JHS has been found in patients presenting to GI clinics with unexplained symptoms. 1 However, the range and prevalence of gastrointestinal (GI) symptoms in JHS patients coming from rheumatology clinics has never been adequately characterised or compared to other patient groups. This was our aim. Methods Multicentre, cross sectional study in new referrals to GI clinics between April 2010 and December 2011. Patients between the ages of 16–70 with a rheumatological diagnosis of JHS were compared to those in whom JHS had been excluded, at their first GI clinic visit. The validated Bowel Disease Questionnaire was completed for GI symptom information. Clinical examination confirmed or excluded the diagnosis of JHS, using the 1998 Brighton criteria. Patients outside the age range or with limited English were excluded. GI symptoms were considered significant if they occurred at least once a week, and were compared between the two groups, adjusting for sex and age. In view of the multiple comparisons, the significance level was set at 0.005. Results 413 patients participated: 43 with a previous rheumatological diagnosis of JHS, and 370 in whom JHS had been excluded. There were significantly more females in the JHS group (95% vs 54%, p=0.000), and they were younger (mean age: 34.6±10.97 vs 43.3±14.2, p=0.000). Abdominal pain was present in all JHS patients and was significantly more likely to be of more than 5 years duration:(OR 4.38 CI 2.1 to 9.1). Other symptoms which were significantly different between the two groups are shown in Abstract PWE-044 table 1. There was no significant difference in the prevalence of constipation (OR 1.1), diarrhoea (OR 0.2), heartburn (OR 1.3), retrosternal chest pain (OR 2), vomiting (OR 1.2), or dyspepsia (OR 2). Conclusion This is the first comparative study of GI symptoms in JHS patients. They have significantly more upper GI symptoms, bloating and alternating bowel habit even when adjusting for age and sex. In view of the association between JHS and unexplained GI symptoms, it is important to consider the diagnosis of JHS in patients with intractable functional GI symptoms, to enable multidisciplinary management. Further studies are needed to determine the mechanism of symptoms in these patients. Competing interests None declared. Reference 1. Zarate N , Farmer AD, Grahame R, et al. Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link? Neurogastroenterol Motil 2009; 22 :252–e78.