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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.

Ehlers–Danlos syndrome (EDS) comprises a group of overlapping hereditary disorders of connective tissue with significant morbidity and mortality, including major vascular complications. We sought to identify the diagnostic utility of a next-generation sequencing (NGS) panel in a mixed EDS cohort. We developed and applied PCR-based NGS assays for targeted, unbiased sequencing of 12 collagen and aortopathy genes to a cohort of 177 unrelated EDS patients. Variants were scored blind to previous genetic testing and then compared with results of previous Sanger sequencing. Twenty-eight pathogenic variants in COL5A1/2, COL3A1, FBN1, and COL1A1 and four likely pathogenic variants in COL1A1, TGFBR1/2, and SMAD3 were identified by the NGS assays. These included all previously detected single-nucleotide and other short pathogenic variants in these genes, and seven newly detected pathogenic or likely pathogenic variants leading to clinically significant diagnostic revisions. Twenty-two variants of uncertain significance were identified, seven of which were in aortopathy genes and required clinical follow-up. Unbiased NGS-based sequencing made new molecular diagnoses outside the expected EDS genotype–phenotype relationship and identified previously undetected clinically actionable variants in aortopathy susceptibility genes. These data may be of value in guiding future clinical pathways for genetic diagnosis in EDS. Genet Med 18 11, 1119–1127.

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 Patients with Ehlers-Danlos syndrome—hypermobility type (EDS-HT) have increased prevalence of gastrointestinal (GI) symptoms, particularly reflux and dyspepsia. EDS-HT is associated with dysautonomia, psychopathology, and chronic pain which can be associated with GI symptoms. The association between GI symptoms and EDS-HT in a ‘non-patient’ population and the effect of the above-mentioned factors has never been studied. Methods In a cross sectional study, a hypermobility questionnaire was used to screen university students; further clinical examination established the diagnosis of EDS-HT. Validated questionnaires assessed for GI, somatic, pain and autonomic symptoms, psychopathology and quality of life (QOL). These were compared in students with and without EDS-HT; logistic regression analysis examined associations between EDS-HT, GI symptoms and other variables. Key Results Of 1998 students screened, 162 were included: 74 EDS-HT (21.0 years, 53% female) vs 88 Non-EDS-HT (21.5 years, 65% female). Compared to non-EDS-HT students, EDS-HT students were more likely to have multiple GI symptoms (41.9% vs 27.3% P=.05), particularly postprandial fullness (34.4% vs 15.9%, P=.01) and early satiety (32% vs 17%, P=.03), greater autonomic (P .8). The association between EDS-HT and postprandial symptoms was dependent on autonomic factors but independent of pain and psychopathology. Pain-related QOL scores were reduced in the EDS-HT group (80 vs 90, P=.03). Conclusions and Inferences The previously described association between EDS-HT, dyspepsia, pain and autonomic symptoms in patients is also present in non-patient groups. Future studies are necessary to explore the etiological role of connective tissue in GI and extra intestinal symptoms.

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.

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Working as a National Health Service rheumatology consultant for the past 30 years I have witnessed the decline of British rehabilitation. As chairman of the Disability Living Allowance Advisory Board since 1993 I have watched an escalation in the cost of disability benefits. Are these two phenomena related?

Three hundred and nineteen UK-based consultant rheumatologists, members of the British Society for Rheumatology (a response rate of 76%), responded to a questionnaire concerning their perceptions of the (benign joint) hypermobility syndrome (HMS). The questions were wide-ranging and covered the nature of the condition, its clinic prevalence, criteria for diagnosis, the efficacy of chosen treatments, the impact of the syndrome on affected individuals and the contribution that it makes to the overall burden of rheumatic disease morbidity. Ninety-two per cent of the respondents believed in the HMS as a distinct clinical entity but only 39% accepted it as a distinct pathological entity. Only 42% were prepared to comment on whether the HMS and Ehlers-Danlos syndrome, hypermobility type (formerly EDS type III) were one and the same entity. There was striking variability in estimated clinic prevalence and no consensus about the diagnostic criteria being used. There was little enthusiasm for treatments currently available. Nearly one-half of the respondents were sceptical about a significant impact of the HMS on people's lives and three-quarters about a significant contribution to the overall burden of rheumatic disease. There was little sign of awareness of findings in recent published studies. It seems unlikely, therefore, that evidence-based medicine is being practised in this area of rheumatology. An unexpected finding was a refreshing enthusiasm for joining regional interest groups on hypermobility (25% of all UK consultants expressed interest).

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.

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.

To define the phenotype of patients with benign joint hypermobility syndrome (BJHS), we studied 58 consecutive patients (mean age 37 yr) presenting to a rheumatology clinic and 30 controls. Patients underwent rheumatological and ophthalmic examination, hypermobility scoring, echocardiography, measurement of bone mineral density (BMD), and skin thickness, elasticity and light transmissibility. The median hypermobility score was 5/9 Beighton and 31/56 Contompasis. Eighteen (31%) patients complained of significant arthralgia. Six (10%) patients and two (7%) controls had mitral valve prolapse (MVP) (chi(2) = 0.27, P = NS). Neither MVP nor aortic diameters showed a correlation with hypermobility score. There was no significant reduction in BMD. There was a significant correlation between hypermobility and light transmissibility of the skin (r = 0.71, P < 0.0001 Contompasis; r = 0.47, P < 0.05 Beighton) and skin stretchiness (r = 0.49, P < 0.05 Contompasis; r = 0.39, P < 0.05 Beighton). On ophthalmic examination, 14 (41%) patients had upper eyelid laxity. Thus, patients with BJHS do not have an increased prevalence of significant cardiac, bone, skin or eye abnormalities, helping differentiate BJHS from other more serious hereditary disorders of connective tissue.

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.

First published online: April 10, 2011

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.

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.

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.

Introduction Joint hypermobility (JHM) refers to the hyperextensibility of joints and is common, with a prevalence of 5–17%.1 It is associated with joint pain but unlike conventional arthropathies, radiological and inflammatory marker abnormalities are absent. JHM tends to be under-diagnosed, even by rheumatologists. Joint pain is common in inflammatory bowel disease (IBD) and is often attributed to seronegative arthropathy. A recent small study suggested that JHM was more common in patients with CD than in UC and healthy controls, and may account for joint pain in these patients.2 Methods We aimed to assess whether: (1) JHM is more common in patients with IBD than in healthy controls. (2) Joint pain is more common in patients with JHM than without. (3) Patients with JHM and joint pain are misdiagnosed as having arthropathies. In a dual-centre prospective observational study in secondary care, 348 follow-up patients (51% female; age range 16–90) attending IBD clinics were asked to complete a validated 5-point JHM questionnaire, and answer questions related to joint pain, previous diagnoses of arthritis and analgesic use. Patients who scored positive on ≥2 hypermobility questions were considered hypermobile. For patients reporting ‘arthritis9, medical records were checked for a rheumatology diagnosis.250 healthy volunteers with no joint pain served as controls. Results 19% patients were hypermobile. There was no difference in the prevalence of JHM in CD (18%) compared to UC (21%) or healthy controls (18%), p=0.49. 56% IBD patients reported joint pain: more patients with JHM (69%) than without (53%, p=0.03) complained of joint pain, but they were less likely to use analgesia (23%) than those without JHM (36%, p Conclusion The prevalence of JHM is not increased in patients with IBD, whether CD or UC. More patients with than without JHM have joint pains but the two groups are equally likely to be diagnosed with arthropathy. Only 1 patient had been diagnosed with hypermobility. Hypermobility seems to be under-diagnosed in patients referred from IBD to rheumatology clinics for assessment of joint pain and should be considered when patients do not clearly satisfy criteria for other arthropathies to ensure they are treated appropriately.

Introduction The Joint Hypermobility Syndrome (JHS) is a relatively frequent inherited connective tissue disorder characterised by marked joint hyperextensibility and extra-articular manifestations. Recent work suggests that gastrointestinal (GI) symptom prevalence may be as high as 86%1 in these patients, and that many of them have evidence of GI dysmotility.2 Dysphagia is a symptom which is not uncommon in these patients, but which has never been formally studied. In general terms, dysphagia is either due to a structural abnormality of the oesophagus or a motility problem. Methods A single-centre retrospective observational study was carried out to characterise the cause of non-structural dysphagia in patients with JHS. JHS patients who were referred to the upper GI physiology unit and who complained of dysphagia were identified. Their HRM and 24-h pH-metry traces were analysed to characterise oesophageal motility, presence of a hiatus hernia, lower oesophageal sphincter (LOS) pressure and presence of gastro-oesophageal reflux (GOR). Results 17 patients with JHS and dysphagia were referred by the rheumatologists to our unit in 1 year: 76% female; age range: 12–58. None had evidence of a structural cause for the dysphagia on either gastroscopy or barium studies. 10 (59%) had an oesophageal dysmotility to account for their dysphagia – out of these one had achalasia; the other 9 (53%) had oesophageal hypomotility with 7 having frequent hypotensive peristalsis and 2 having intermittent hypotensive peristalsis. 33% of those with hypomotility had a normal Multiple Rapid Swallow test (MRS). 7 of the 17 patients (41%) had normal oesophageal motility and 6 of these had reflux studies: 50% had GOR, 17% had a hypersensitive oesophagus and the remaining 33% had normal studies. Only 2 patients (12%) had hiatus hernias and both of these had oesophageal hypomotility and no GOR. Conclusion This is the first study of upper GI physiology in patients with JHS and non-structural dysphagia. Oesophageal hypomotility is common in these patients and those patients with normal MRS are likely to show the best response to prokinetics. 50% of those with normal motility had pathological GOR and would benefit from high dose proton pump inhibitor therapy. The remainder had normal studies, suggesting hypersensitivity which may respond to treatment with neuromodulators such as amitriptyline. Only 12% of patients had a hiatus hernia, which is in contrast to previous studies.3 Further prospective studies are required to understand the pathophysiology and management options for dysphagia in JHS.

Joint hypermobility syndrome (JHS), previously known as benign joint hypermobility syndrome (BJHS), is a heritable disorder of connective tissue that comprises symptomatic hypermobility predisposing to arthralgia, soft tissue injury, and joint instability.1 It is indistinguishable from the hypermobility type of Ehlers-Danlos syndrome.2 Complications may include autonomic dysfunction, proprioceptive impairment, premature osteoarthritis, intestinal dysmotility, and laxity in other tissues causing hernias or uterine or rectal prolapse. Symptoms are often minimal or mild, but 168 out of 700 patients with joint hypermobility syndrome (24%) attending the UCH Hypermobility Clinic already had an established chronic pain syndrome at the time of their first outpatient attendance. These patients were experiencing serious pain, disability, and impairment of the quality of life, some patients becoming chairbound or even bedbound.3 #### Case scenario A 30 year old project manager, who is new to your general practice, presents with right anterior knee pain after slipping and landing on his knee three months ago. Imaging shows no abnormality, but he describes a long history of recurrent shoulder subluxation, and many soft tissue problems and joint pains, often after similarly trivial trauma, and he states that imaging and blood tests “for arthritis” have always been normal. You note that he has no signs of inflammation but that he is hypermobile according to the Beighton score (see box 1), and looking up the Brighton criteria, which includes and extends the older Beighton score (see box 2), you mention he fulfils the criteria for joint hypermobility syndrome, and he expresses relief there is an explanation for his symptoms. #### Box 1 Nine-point Beighton score for joint hypermobility syndrome4 One point is gained for each side of the body for the first four manoeuvres listed below, such that the hypermobility score is a maximum of 9 if all are positive.

PROFESSOR Grahame welcomed everybody to the third meeting of this special interest group that has run concurrently with the Annual General Meeting. The meeting was opened by Dr Ann Child, who gave a well-illustrated overview of her continued research interests into the microfibril glycoprotein fibrillin. There are now up to 40 fibrillin gene mutations in classical Marfan's syndrome. A recent study of Marfan's syndrome has demonstrated that both hypermobile and female subjects have a better long-term prognosis in respect to cardiovascular involvement than those subjects with stiff contracted joints. Increasing numbers of microfibril-associated proteins and mutations within them are being described each year. This has led to a group of parallel studies searching for fibrillin mutations in individuals who have features associated with Marfan's syndrome. These include the benign joint hypermobility syndrome, ectopia lends, mitral valve prolapse, congenital contractural arachnodactyly (Beal's syndrome) and scoliosis. Mutations have been identified in the fibrillin genes situated on chromosomes 5, 15, 17 in eight families with the benign joint hypermobility syndrome. A study of 90 consecutive patients with mitral valve prolapse revealed Marfanoid features in 75%, skeletal signs in 72%, skin extensibility in 58% and joint hypermobility syndrome in 5%. Up to 80% of Marfan's patients have some degree of lens dislocation and therefore a group of 11 families with dominantly inherited ectopia lentis were studied further. Significant joint hypermobility was seen in four families and mild mitral valve prolapse in four families. An associated mutation in the FBN1 gene has since been described in one of these ectopia lentis families. Defects in a second fibrillin gene, FBN2 (located on chromosome 5), have recently been demonstrated in congenital contractural arachnodactyly. A plea was made for referral of further cases so that this condition could be studied further. Scoliosis is frequently associated with Marfan's syndrome. The inheritance of 40 families with isolated scoliosis would appear to be dominant, but sex influenced, with reduced penetrance in up to one-third of family members. Joint hypermobility is found in one-third of these famines. Defective incorporation of fibrillin into the extracellular matrix was seen in four out of a subset of seven of these cases. Further linkage studies of genes in the fibrillin and elastin families are under way. Each year increased numbers of fibrilassociated proteins are discovered, which could also be candidates for linkage studies into the overlapping inherited connective tissue diseases. In discussion, Dr Paul Wordsworth again stressed the underlying problem of accurately denning the phenotype in this group of patients before linkage studies are performed, and Likened it to osteogenesis imperfecta where mild and severe cases frequently occur within one family. The second presentation, by Dr Lee Hardwick, gave an excellent overview of the principles behind linkage studies and the new methods available for speeding up this process. Three major types of genetic markers have been used over the last 10-15 yr, firstly restriction fragment length polymorphisms (RFLPs), then minisatelh'tes and, more recently, microsatellites. One disadvantage of using the tandom repeats of minisatelhtes is that they are not evenly distributed throughout the genome and are thus not closely associated with individual genes. The microsatellites (dinucleotide repeats) are situated between genes and are evenly distributed throughout the genome. This makes them highly informative and they are therefore the markers of choice. The polymerase chain reaction can be used to amplify dinucleotide repeats and therefore across specific regions of the genome. Fluorescent rather than radioactive tags are now available which enable automatic reading of computergenerated gel images, increasing the speed at which the genome can then be analysed. These new technologies have been used to revisit the collagen genes in Ehlers-Danlos syndrome and possible linkage to the short arms of chromosomes 17, 7 and 2, which contain COL1A1, COL1A2 and COL1A3, respectively. It is now possible to use microsatellite repeats that span the whole genome to determine where the abnormal gene within these famines is segregating. There are plans to study further large families and it is hoped the precise linkage will soon be established.