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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.

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 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.

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.

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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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?

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

This chapter seeks to draw readers' attention to the importance of the heritable disorders of connective tissue in clinical practice. It describes the principal features of the Marfan and Ehlers–Danlos syndromes, osteogenesis imperfecta and benign joint hypermobility syndrome, their clinical and prognostic similarities and differences, and their distinguishing features. Recently revised international classifications drawing on advances in molecular genetics are described in detail. Wherever possible, patients' symptoms are explained on the basis of the altered biomechanics of genetically aberrant connective tissue matrix proteins. Finally, the chapter draws attention to the often unrecognized burden of chronic pain borne by patients with these conditions, a feature of which many rheumatologists seem unaware, and sets out a rational and holistic approach to treatment and management that is based on the best currently available evidence.

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.

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.

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.

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)

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.

Joint hypermobility is widely prevalent in all communities yet its clinical effects are poorly understood and often overlooked by rheumatologists worldwide. They may observe the hypermobility but fail to appreciate its significance in terms of overall morbidity and, more specifically, its strong link with chronic pain, fatigue, dysautonomia and the adverse impact on quality of life.This last year's publications shed further light on this fascinating and, as yet, largely unexplored terrain within rheumatology. Perhaps the most compelling new knowledge is the finding that hypermobility, if sought, is the most common finding amongst patients presenting to a rheumatologist; more often than not, it is being overlooked. There is an urgent need for rheumatologists to accept the challenges posed by hypermobility-related disorders, which have, in the past, fallen by default to clinical geneticists untrained in rheumatology.Hypermobility, a largely unacknowledged though epidemiologically important area within rheumatology, affects almost every bodily system. Recent medical literature attests to the breadth of clinical science encompassed by the seemingly trivial term, hypermobility. Drawing readers' attentions to this fascinating, challenging, but neglected area of rheumatology will hopefully entice them to explore these conditions with greater zeal.

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.

To ascertain the prevalence of hypermobility and the benign joint hypermobility syndrome (BJHS) in male and female student and professional ballet dancers, and explore whether BJHS has any effect on a dance career.Students from the Royal Ballet School and professional dancers from the Royal Ballet Company, London, were compared with a control group of teenagers and adults from a local secondary school and The Royal Opera House, respectively. The data, examined by variance analysis, included anthropometric variables, the Beighton score, and clinical features constituting BJHS. Odds ratios for hypermobility and BJHS in dancers were calculated, and the prevalence and distribution of BJHS was examined.Hypermobility and BJHS were common in male and female dancers compared with controls. An OR of 11.0 (95% CI 3.3-31.8) was found for hypermobility in dancers for both the ballet school and the professional company. The prevalence of BJHS was found to decline both from student to professional and within the ballet company from corps de ballet to Principal. Odds ratios for BJHS in student dancers were significant, OR = 3.9 (95% CI 1.3-11.3), but not so in professional dancers: OR = 1.7 (95% CI 0.6-4.7). Arthralgia was common in dancers and was reported more often in males than females. In females, pain was reported most by dancers with other features of BJHS, in particular stretchy skin.Hypermobility and BJHS are common in both male and female student and professional ballet dancers. The fall in prevalence, and the greater reporting of arthralgia with other features of BJHS in young female dancers, suggests that BJHS may have an important negative influence, and this may have implications for training. The same pattern was not observed in males, suggesting that their pain-reporting and injury are related to factors other than BJHS.

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.

The prevalence of hypermobility and its consequence in an aging female population is unknown. Case studies of patients with the benign joint hypermobility syndrome suggest both a tendency toward osteopenia and an association with premature osteoarthritis (OA). We assessed hypermobility and its relationship to bone mineral density (BMD) and OA in a postmenopausal female community population.Joint hypermobility was assessed by the Beighton and the (more quantitative) Contompasis scores in 716 female subjects under followup in the Chingford Study (age range 53-72, mean 61 yrs, SD 5.8).We found 79 of 716 subjects (11%) had a hypermobility score1/9 on the Beighton scale (spine in 75/79); 82/716 had a Contompasis score22 (normal18). Only one had a 4/9 Beighton score indicative of generalized joint hypermobility. Subjects with Contompasis22 were more physically active and less likely to smoke. They had a reduced risk of knee OA (joint space narrowing) (OR 0.48, 95% CI 0.27-0.83, after adjusting for age, height, weight, and activity), but no change in risk of OA in spine or hands. Hip BMD was increased by 3% in this more hypermobile subgroup (p0.05). A similar effect was seen for knee OA, but not BMD in those with a Beighton score1.Our data suggest that in this postmenopausal population the tendency to joint hypermobility may be a marker for fitness, manifested by reduced knee OA and increased hip BMD. The incidence of generalized hypermobility (Beighton4/9) was very low (0.14%) compared with the localized form (seen in 11%) and other studies. Those with mild degrees of hypermobility showed no evidence of premature OA or reduced BMD, as reported in some of the rarer heritable disorders of connective tissue.

Background: Connective tissue disorders, such as some forms of Ehlers-Danlos syndrome, have been associated with severe periodontitis. Methods: This report describes a case of Marfan's syndrome, an inherited disorder of connective tissue caused by mutations in the fibrillin-1 gene, in which the patient presented with severe periodontitis. Results: At examination, an average full-mouth clinical attachment level loss of 5.6 ± 2.1 mm, furcation involvement, and severe alveolar bone loss were observed in a 41-year-old Caucasian male. Tooth hypermobility was also present. Conclusions: This case appears to be the first documentation of severe periodontitis in a patient with Marfan's syndrome. It supports the hypothesis that a variety of connective tissue disorders may confer increased susceptibility to periodontal tissue breakdown. J Periodontol 2002;73:823-826.

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.

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.

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.

Epidural corticosteroid injection is a relatively effective treatment for low back pain and sciatica with a low incidence of side effects, although the patient's perspective in terms of outcome and satisfaction has not been studied well. The assessment of outcome in low back pain patients is complex. Three types of measure were compared: 1) a clinical score, 2) patient ratings of pain and disability, and 3) patient satisfaction ratings. There were significant discrepancies among the results. Consequently, clinical trials using different outcome measures may reach different conclusions. It therefore is vital to have planned the study carefully in advance, considering the questions to be asked, especially in this area, where patient-derived measures (e.g., "patient satisfaction") are so important. This study of 35 patients showed a fall in clinical signs/symptoms, disability, and pain 1 week after the injection, with maintenance of the reduction in disability at 3 months. Eighty-five percent reported at least some improvement at 1 week and 43% had improvement lasting 3 months. Patients with a more depressed mood had higher levels of disability both before and after the procedure. Anxiety before the procedure did not adversely affect outcome, and it was well tolerated by most patients. At 3 months 83% were satisfied with the treatment they had received and a patient satisfaction questionnaire gave similar results. We continue to recommend this treatment as a well-tolerated procedure, with which most patients are satisfied.

Cardiac abnormalities are a recognised feature of connective tissue disorders. We report a case of Ehlers-Danlos syndrome associated with an aneurysm of the membranous ventricular septum and mitral valve prolapse. To our knowledge this is the first reported association of Ehlers-Danlos syndrome and ventricular septal aneurysm.

Six patients with rheumatoid arthritis were treated with a CD7 mouse monoclonal antibody, RFT2, daily for 15 days. Only two patients had a significant improvement in clinical disease activity which lasted 7-14 days. No serious adverse effects occurred although all patients developed antibodies against mouse immunoglobulin. During treatment T-lymphocyte numbers decreased and T-lymphocyte CD7 expression was absent in all but one patient.

Sulindac (400 mg/day) has been compared with ibuprofen (1200 mg/day) in 40 patients with osteoarthrosis of the hip, over an eight-week period, in a double-blind controlled clinical trial. The two drugs were comparable in terms of patient preference, effects on hip movements, and toxicity. Sulindac showed superior analgesic properties to ibuprofen, resulting in a significantly greater reduction in pain on weight-bearing and with passive movements (P less than 0.01).

The value of epidural injections of corticosteroid as an outpatient treatment of sciatica has been hitherto uncertain. An epidural injection of 80 mg methylprednisolone in 10 ml physiological saline was compared with an interspinous injection of 2 ml physiological saline in a double blind fashion amongst 39 outpatients. Significant differences of pain relief were seen between the two groups within 2 weeks. This benefit disappeared for six (35%) patients within 6 months of treatment although 11 (65%) successfully treated subjects had sustained improvement up to this time. Outpatient epidural injections of corticosteroid are thus a useful short-term means of relieving pain in sciatica but probably have little effect on the long-term natural history of symptoms. Factors associated with a failure to respond to epidural steroid injections are discussed.

Forty-seven patients with active rheumatoid arthritis took part in an 8-week controlled study in which clotrimazole was compared with a standard nonsteroidal anti-inflammatory agent, ketoprofen. Although clotrimazole was shown to be effective in the treatment of the disease and superior to ketoprofen in certain measurements, if was also responsible for a high incidence of adverse effects. Improvement with clotrimazole took place more slowly but was more sustained than with ketoprofen. A significant rise in plasma cortisol and a fall in white cell count was observed in the clotrimazole treated patients.

In this paper we report the use of the technetium-99m diphosphonate bone scan in the diagnosis and management of traumatic bone lesions in the ballet dancer's foot. Nine illustrative case histories are given. We conclude that this is a useful technique particularly in the recognition of stress lesions not identified by conventional radiography.

A survey of joint mobility was conducted in 295 healthy children between the ages of 5 and 10 years who attended a London primary school. Estimates of the commonly used measurements, that is passive dorsiflexion of the wirsts and ankles, passive hypertension of the elbows and knee, were too insensitive to detect any age effect. However, a method of estimating extensibility of the 5th metacarpophalangeal joint in response to a standard load detected a highly significant inverse correlation between joint mobility and age in the samples significant inverse correlation between joint mobility and age in the samples tested ( r = -0.586; P less than 0.0001). There was no apparement sex difference. Skinfold thickness using the Harpenden caliper over the 3rd metacarpal bone and the in vivo skin elasticity measured using a suction cup device performed on a sample of 78 of the children revealed no influence of either age or sex on these parameters. This is in sharp contradistinction to the effect of both age and sex in these two parameters in adults...

A double-blind cross-over study of cyclofenil and placebo treatments was conducted in 11 scleroderma patients. Each treatment period was for four months. A range of subjective and objective measurements failed to reveal any consistent or obvious response to cyclofenil. One patient died of his disease during active treatment. Four were withdrawn because of liver dysfunction which was attributed to cyclofenil. It remains to be seen whether treatment over longer periods will exert a clinically significant effect.