Genetic complexity of diagnostically unresolved Ehlers-Danlos syndrome.

BACKGROUND: The Ehlers-Danlos syndromes (EDS) are heritable disorders of connective tissue (HDCT), reclassified in the 2017 nosology into 13 subtypes. The genetic basis for hypermobile Ehlers-Danlos syndrome (hEDS) remains unknown. METHODS: Whole exome sequencing (WES) was undertaken on 174 EDS patients recruited from a national diagnostic service for complex EDS and a specialist clinic for hEDS. Patients had already undergone expert phenotyping, laboratory investigation and gene sequencing, but were without a genetic diagnosis. Filtered WES data were reviewed for genes underlying Mendelian disorders and loci reported in EDS linkage, transcriptome and genome-wide association studies (GWAS). A genetic burden analysis (Minor Allele Frequency (MAF) <0.05) incorporating 248 Avon Longitudinal Study of Parents and Children (ALSPAC) controls sequenced as part of the UK10K study was undertaken using TASER methodology. RESULTS: Heterozygous pathogenic (P) or likely pathogenic (LP) variants were identified in known EDS and Loeys-Dietz (LDS) genes. Multiple variants of uncertain significance where segregation and functional analysis may enable reclassification were found in genes associated with EDS, LDS, heritable thoracic aortic disease (HTAD), Mendelian disorders with EDS symptomatology and syndromes with EDS-like features. Genetic burden analysis revealed a number of novel loci, although none reached the threshold for genome-wide significance. Variants with biological plausibility were found in genes and pathways not currently associated with EDS or HTAD. CONCLUSIONS: We demonstrate the clinical utility of large panel-based sequencing and WES for patients with complex EDS in distinguishing rare EDS subtypes, LDS and related syndromes. Although many of the P and LP variants reported in this cohort would be identified with current panel testing, they were not at the time of this study, highlighting the use of extended panels and WES as a clinical tool for complex EDS. Our results are consistent with the complex genetic architecture of EDS and suggest a number of novel hEDS and HTAD candidate genes and pathways.

The 2017 international classification of the Ehlers-Danlos syndromes.

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. © 2017 Wiley Periodicals, Inc.

A framework for the classification of joint hypermobility and related conditions.

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.

Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history.

The hypermobile type of Ehlers-Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue. It has been described largely in those with musculoskeletal complaints including joint hypermobility, joint subluxations/dislocations, as well as skin and soft tissue manifestations. Many patients report activity-related pain and some go on to have daily pain. Two undifferentiated syndromes have been used to describe these manifestations-joint hypermobility syndrome and hEDS. Both are clinical diagnoses in the absence of other causation. Current medical literature further complicates differentiation and describes multiple associated symptoms and disorders. The current EDS nosology combines these two entities into the hypermobile type of EDS. Herein, we review and summarize the literature as a better clinical description of this type of connective tissue disorder. © 2017 Wiley Periodicals, Inc.

A connective tissue disorder may underlie ESSENCE problems in childhood.

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.

Ehlers-Danlos Syndrome-Hypermobility Type: A Much Neglected Multisystemic Disorder.

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.

Targeted next-generation sequencing makes new molecular diagnoses and expands genotype-phenotype relationship in Ehlers-Danlos syndrome.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

How do people with chronically painful joint hypermobility syndrome make decisions about activity?

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.

Efficacy of an out-patient pain management programme for people with joint hypermobility syndrome.

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 < 0.001). Although by 5 months all these outcomes had regressed towards pre-programme levels there remained significant improvements compared to baseline in all except average pain intensity. This open study shows that patients with JHS experienced significant benefits after attending a JHS-specific pain management programme, which were still evident 5 months later. Longer-term controlled studies are required.

A prospective evaluation of undiagnosed joint hypermobility syndrome in patients with gastrointestinal symptoms.

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.

Joint hypermobility: emerging disease or illness behaviour?

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.

Joint hypermobility syndrome.

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--a key to diagnosing heritable disorders of connective tissue.

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.

Postural tachycardia syndrome--current experience and concepts.

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.