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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: 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.

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

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

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

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

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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

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).

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.

Resume La douleur est presente chez de nombreux patients souffrant d'un syndrome d'hyperlaxite, le plus frequent d'entre-eux etant le syndrome d'hypermobilite articulaire benigne (SHAB). Ces patients peuvent aussi avoir des problemes psychosociaux, qui retentissent sur leur sante. Le principal symptome reste la douleur articulaire, musculaire ou ligamentaire, renforcant les consequences de microtraumatismes repetes ; d'autres facteurs sont egalement associes comme l'arthrose ou la fibromyalgie. Les facteurs neurophysiologiques pourraient se comporter ici comme des stimuli nociceptifs. La douleur et la souffrance d'origine viscerale peuvent resulter d'une laxite du tissu conjonctif thoracique, abdominal ou pelvien entrainant prolapsus uterin ou rectal, prolapsus de la valve mitrale, ou pneumothorax spontane. Chez des enfants, l'hyperlaxite articulaire est un facteur important et souvent meconnu des symptomes rhumatologiques, ignore ou mis a tort sur le compte d'un rhumatisme inflammatoire. La prise en charge de la douleur et de la gene des syndromes d'hyperlaxite requierent connaissance, patience, compassion et comprehension. Souvent les resultats des traitements classiques (medicamenteux ou chirurgicaux), comme ceux que l'on utilise pour d'autres affections rhumatologiques, sont decevants ; des approches innovantes sont necessaires. Parmi celles-ci, pour laquelle quelques resultats demontres ont ete obtenus, on peut citer la physiotherapie, la prescription d'ortheses, la reeducation proprioceptive, et des techniques plus recentes de prise en charge de la douleur comme les therapies cognitives comportementales.

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

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

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

Hypermobility-related syndromes constitute a family of heritable disorders of connective tissue (HDCT) that derive from abnormalities affecting genes that encode for the connective tissue matrix proteins such as collagen, fibrillin, and tenascin. They range from such commonplace though poorly recognized conditions such as hypermobility spectrum disorder (HSD), formerly within the joint hypermobility syndrome (JHS), to the better-known, if rarer, eponymous syndromes such as the Marfan syndrome (MFS), Loeys–Dietz syndrome, and the different types of the Ehlers-Danlos syndrome (EDS). The more common presentations are with skin pathology (bruising, scaring), joint or spinal and/or muscle pain and instability with vulnerability to injury and chronic widespread pain, cardiac valve pathologies, and in MFS and vascular EDS, in particular, arterial dilatation with the risk of dissection and rupture. The hypermobile variant of EDS and HSD are further complicated by cardiovascular autonomic dysfunction such as orthostatic intolerance, palpitations, and syncope, and the recently described and commonly encountered pan-gastrointestinal dysmotility. The latter can manifest as gastro-oesophageal reflux, gastroparesis, slow-transit constipation, or rectal evacuatory dysfunction with rectal intussusception. In addition, HDCT are associated with bladder and uterine problems as a consequence of pelvic floor weakness. Such multisystemic conditions need to be managed by a multidisciplinary team able to draw on medical, surgical, physical, and psychological interventions by appropriately experienced specialists and therapists. This chapter introduces the reader to the epidemiology, genetics, classification, and clinical presentation of HSD, EDS, and MFS. It also describes the key investigations required to support a diagnosis and assess complications of an HDCT, as well as the multidisciplinary approach to management.

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)

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

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

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

This edition, the fourth in a series spanning some 25 years since the publication of the first edition in 1983, is likely to be the last prepared under the current authorship. In addition to chronicling further progress in the field, it seems appropriate to add a final chapter concerning areas that might be suitable, even ripe, for translational research in the future. This chapter, at times unashamedly speculative, synthesises the ideas of all three authors, each approaching the field from their slightly different perspectives. We apologise to readers if some of our suggestions prove impractical or if we have failed to consider their own areas of particular interest in this wide field.

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

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

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

Arguably, the most surprising development of the past decade has been the realisation that the effects of JHS do not lie exclusively within the confines of the musculoskeletal system. Nowadays, it is no exaggeration to state that JHS is seen as a multi-facetted multi-system disorder which effectively touches virtually all medical specialties in one way or another.

First published online: April 10, 2011