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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

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.

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.