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Dysautonomia (autonomic dysfunction) occurs in the Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Symptoms include palpitations, dizziness, presyncope, and syncope, especially when standing upright. Symptoms of orthostatic intolerance are usually relieved by sitting or lying and may be exacerbated by stimuli in daily life that cause vasodilatation, such as food ingestion, exertion, and heat. Neurocardiovascular dysautonomia may result in postural tachycardia syndrome (PoTS), a major cause of orthostatic intolerance. It is defined by a rise in heart rate of >30 beats per minute (bpm) in adults and >40 bpm in teenagers while upright, without a fall in blood pressure (BP; orthostatic hypotension). In some, it can be compounded by the presence of low BP. For many, there is delay in clinicians recognizing the nature of the symptoms, and recognizing EDS or HSD, leading to delays in treatment. The onset of PoTS may be linked to an event such as infection, trauma, surgery, or stress. Gastrointestinal and urinary bladder involvement may occur, along with thermoregulatory dysfunction. In some, the mast cell activation syndrome may be contributary, especially if it causes vasodilatation. This paper reviews neurocardiovascular dysautonomia with an emphasis on PoTS, its characteristics, associations, pathophysiology, investigation, and treatment.

In late 2017, the global nonprofit, The Ehlers-Danlos Society (TEDS), was awarded a "Pipeline to Proposal" Tier A award from the Patient-Centered Outcomes Research Institute (PCORI). The goal of this application was to form a team of patients, researchers, other community support groups and stakeholders who are focused on establishing the Ehlers-Danlos Comorbidity Coalition to address the common health issues associated with this group of high morbidity, high disease burden conditions. The ongoing Coalition that is now funded by individual donors and expanding in its mission and members, is an example of successful collaboration spanning over borders and priorities.

The 2017 classification of Ehlers-Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re-define this OI/EDS overlap as a missing EDS type. Twenty-one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS-related features. OI-related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N-proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.

Context The Ehlers-Danlos Syndromes (EDSs) are a set of rare heritable disorders of connective tissue, characterized by defects in the structure and synthesis of extracellular matrix elements that lead to a myriad of problems including joint hypermobility and skin abnormalities. Because EDS affects multiple organ systems, defining clear boundaries and recognizing overlapping clinical features shared by disease phenotypes is challenging. Objectives The objective of this study was to seek evidence of phenotypic subgroups of patients with distinctive symptom profiles and describe these resulting subgroups. Methods Data were extracted from a repository assembled 2001–2013 by the National Institute on Aging Intramural Research Program. Agglomerative hierarchical clustering was used to form distinct subgroups of patients with respect to the domains of pain, physical and mental fatigue, daytime sleepiness, and nighttime sleep. Domains were selected based on literature review, clinician expertise, and guidance from patient advisors. Results One hundred seventy-five patients met all inclusion criteria. Three subgroups were identified. The Pain Dominant subgroup (39 patients) had the highest mean pain values, but lowest mean values of other symptoms. The High Symptom Burden subgroup (71 patients) had high mean values in all domains. The Mental Fatigue subgroup (65 patients) had a high mean value for mental fatigue and daytime sleepiness, but a lower mean value for pain. Conclusion The subgroups aligned with clinical observation of the heterogeneous nature of EDS, with overlapping symptoms between subtypes and a wide divergence in degree of symptoms within subtypes. This exploratory study helps characterize the various phenotypes and comorbidities of patients with EDS.

Background/Aims The Ehlers-Danlos Society is an affiliate of Project ECHO, a non-profit organisation supporting health professionals manage their patients through telehealth case-based learning. To increase access to expert advice and learning, in 2019 the Ehlers-Danlos Society introduced EDS ECHO, a series of programmes for health professionals supporting them in learning and sharing knowledge in the management of Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Programmes run from the UK, USA, and Australia; participants and experts joining from all over the world, and, from multiple specialties. This study explores participant perceptions of a 9-session programme covering all aspects of diagnosis and management in EDS and HSD, and, their co-morbidities. Each session is 90 minutes long, providing a total of 13.5 hours of learning. All materials are made available for review. The programme is repeated throughout the year. Methods The study had IRB approval from Penn State, USA. At the beginning of each 9-session programme, participants were invited to join the study. Using REDCap, a series of questions surveyed the participants confidence in managing patients with EDS or HSD; and, re-explored this at 6 months following completion of the programme. In addition, participants were surveyed for their perceptions of the value of the programme. Results 185 of 237 eligible participants completed the baseline and 6-month follow-up survey. At baseline 17%, 47%, and 36% reported their levels of confidence in diagnosing EDS or HSD as either low, moderate, or high respectively. The most reported motivations for joining the programme were: to increase knowledge (90% of responders), access experts (71%), and, increase confidence in managing EDS and HSD (68%). At 6-month follow-up 80-95% of participants reported positive experiences across the various fields of enquiry. With regard to increasing level of knowledge 46% reported a 'slight' increase and 46% a 'great' increase. Levels of confidence in diagnosis and management had risen 'slightly' in 54% and 'greatly' in 40% of participants. 78% of participants reported an overall increase in their interest in EDS and HSD. Conclusion The Project ECHO model of 'all teach all learn', case-based learning, and use of telehealth technology is well-established in supporting healthcare professionals managing patients across the breadth of Medicine. EDS ECHO follows these principles and practices, providing a series of programmes aligned to the multiple disciplines that manage people with EDS and HSD. For the majority of participants their perception was that the EDS ECHO 9-week program increased their knowledge and confidence in assessing and managing EDS and HSD. Further analysis will explore themes for developing the program, and how changes in confidence are influenced by baseline perceptions. In addition, a study is underway to explore perceptions of care among patients of participants in the EDS ECHO programme. Disclosure A. Hakim: Consultancies; The Ehlers-Danlos Society. J. Schubart: Grants/research support; The Ehlers-Danlos Society. C. Francomano: Grants/research support; The Ehlers-Danlos Society. R. Bascom: None. L. Bloom: Corporate appointments; The Ehlers-Danlos Society.

Chronic fatigue is an important contributor to impaired health-related quality of life in Ehlers-Danlos syndrome. There is overlap in the symptoms and findings of EDS and chronic fatigue syndrome. A proportion of those with CFS likely have EDS that has not been identified. The evaluation of chronic fatigue in EDS needs to include a careful clinical examination and laboratory testing to exclude common causes of fatigue including anemia, hypothyroidisim, and chronic infection, as well as dysfunction of major physiological or organ systems. Other problems that commonly contribute to fatigue in EDS include sleep disorders, chronic pain, deconditioning, cardiovascular autonomic dysfunction, bowel and bladder dysfunction, psychological issues, and nutritional deficiencies. While there is no specific pharmacological treatment for fatigue, many medications are effective for specific symptoms (such as headache, menstrual dysfunction, or myalgia) and for co-morbid conditions that result in fatigue, including orthostatic intolerance and insomnia. Comprehensive treatment of fatigue needs to also evaluate for biomechanical problems that are common in EDS, and usually involves skilled physical therapy and attention to methods to prevent deconditioning. In addition to managing specific symptoms, treatment of fatigue in EDS also needs to focus on maintaining function and providing social, physical, and nutritional support, as well as providing on-going medical evaluation of new problems and review of new evidence about proposed treatments. © 2017 Wiley Periodicals, Inc.

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) is a heterogeneous heritable disorder of connective tissue characterised by hypermobilityof the joints, skin hyperextensibility and tissue fragility. It does not have racial or gender predilection. The Villefranche classification divides it into six major forms: classic, hyper-mobility, vascular, kyphoscoliosis, arthrochalasia and der-matosparaxis1(Table 1), replacing the older nosology that described types I–XI.2Most patients have a normal or near-normal life expectancy, with variable morbidity. However,the vascular type is associated with the serious complications of spontaneous arterial rupture and visceral perforation.

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.

© 2014 IOS Press and the authors. BACKGROUND: Generalised joint hypermobility (GJH) is common in the general population and may not confer any adverse symptoms. Joint Hypermobility Syndrome (JHS) is a connective tissue disorder that often runs in families and may present with a complex array of signs and symptoms. JHS is under-recognised and often poorly managed by the medical and physiotherapy professions. OBJECTIVES: The primary aim of this study was to investigate the prevalence of GJH and JHS in patients attending a Musculoskeletal Triage Clinic. Secondary aims of this study were to explore the health-related quality of life, pain levels, primary pain area and number of painful joints in patients with and without JHS. METHOD: A cross-sectional study design was used. The participant population included a convenience sample from patients attending a Musculoskeletal Triage Clinic based in a Primary Care setting in London. The main outcome tools were the Beighton Score, Brighton Criteria, the EQ-5D-5 L and the Visual Analogue Scale (VAS). RESULTS: A total of 150 participants were recruited into the study. GJH was recorded in 19% of participants and JHS was recorded in 30% of participants. Participants with JHS reported a greater number of painful joints (p < 0.05) than those without. No difference was found in the EQ-5D-5 L and the global VAS scores between the group with JHS and the group without. Participants with JHS (p < 0.01) were found to be more likely to present with wrist/hand pain as their main problem compared to those without JHS. CONCLUSIONS: This study found GJH in 19% and JHS in 30% of participants attending a Musculoskeletal Triage Clinic. This study also found that patients with JHS are likely to present with a greater number of painful joints and are more likely to present with wrist/hand pain as their main problem than those without JHS.

Purpose: To explore exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers–Danlos syndrome – hypermobility type and to explore patient experiences of physiotherapy. Methods: A cross sectional questionnaire survey design was used to collect quantitative and qualitative data from adult members of the Hypermobility Syndromes Association and Ehlers–Danlos Syndrome Support UK. Descriptive and inferential statistics were used to analyse the data. Qualitative data was analysed thematically. Results: 946 questionnaires were returned and analysed. Participants who received exercise advice from a physiotherapist were 1.75 more likely to report high volumes of weekly exercise (odds ratio [OR] = 1.75, 95% confidence interval [CI] = 1.30–2.36, p p = 0.004). Three themes emerged regarding experience of physiotherapy; physiotherapist as a partner, communication – knowledge, experience and safety. Conclusion: Pain, fatigue and fear are common barriers to exercise. Advice from a physiotherapist and beliefs about the benefits of exercise influenced the reported exercise behaviours of individuals with Ehlers–Danlos syndrome – hypermobility type in this survey.Implications for rehabilitationExercise is a cornerstone of treatment for Ehlers–Danlos syndrome/Ehlers–Danlos syndrome – hypermobility type.Pain, fatigue and fear of injury are frequently reported barriers to exercise.Advice from physiotherapists may significantly influence exercise behaviour.Physiotherapists with condition specific knowledge and good verbal and non-verbal communication facilitate a positive therapeutic experience. Exercise is a cornerstone of treatment for Ehlers–Danlos syndrome/Ehlers–Danlos syndrome – hypermobility type. Pain, fatigue and fear of injury are frequently reported barriers to exercise. Advice from physiotherapists may significantly influence exercise behaviour. Physiotherapists with condition specific knowledge and good verbal and non-verbal communication facilitate a positive therapeutic experience.

Background: Rituximab (RTX) in combination with methotrexate (MTX) has been licensed since 2006 for the management of severe active rheumatoid arthritis (RA) in patients who have failed at least one anti-tumour necrosis factor (anti-TNF) therapy. Published clinical trials have demonstrated the efficacy of RTX in improving both clinical symptoms and patients' physical function. This study aimed to assess the effectiveness of RTX in RA patients treated in routine clinical practice by examining clinical and patient reported outcomes six months after receiving a first course of RTX. Methods: The analysis involved 550 RA patients registered with the BSRBR, who were starting RTX and were followed up for at least 6 months. Change in Disease Activity Score (DAS28) and European League Against Rheumatism (EULAR) response were used to assess the clinical response while change in Health Assessment Questionnaire (HAQ) score was used to assess the physical function of the patients 6 months after starting RTX. The change in DAS28 and HAQ was compared between seronegative and seropositive patients and anti-TNF naïve patients versus anti-TNF failures. The response was also compared between patients receiving RTX in combination with MTX, other non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) or no nbDMARDs. Results: The mean (s.d.) age of the cohort was 59 (12) years and 78% of the patients were females. The patients had a mean (s.d.) of 15 (10) years of disease duration. 16% were biologic naïve while 84% were anti-TNF failures. 32% of the patients were seronegative and 68% were seropositive. The mean (95% CI) DAS28 at baseline was 6.2 (6.1, 6.3) which decreased to 4.8 (4.7, 4.9) at 6 months of follow up. 16% were EULAR good responders, 43% were moderate responders and 41% were non responders. The mean (95% CI) change in HAQ was −0.1 (−0.2, −0.1) (Table 1). The mean change in DAS28 was similar in seropositive and seronegative patients (p = 0.18) while the anti-TNF naïve patients showed a greater reduction in DAS28 scores than anti-TNF failures (p = 0.05). Patients receiving RTX in combination with MTX showed similar changes in DAS28 and HAQ compared to patients receiving RTX alone or with other nbDMARDs. Conclusions: RTX has proven to be effective in the routine clinical practice. Anti-TNF naïve patients seem to benefit more from RTX treatment than anti-TNF failures. Disclosure statement: The authors have declared no conflicts of interest

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

Autonomic dysfunction contributes to health-related impairment of quality of life in the hypermobile type of Ehlers-Danlos syndrome (hEDS). Typical signs and symptoms include tachycardia, hypotension, gastrointestinal dysmotility, and disturbed bladder function and sweating regulation. Cardiovascular autonomic dysfunction may present as Orthostatic Intolerance, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, or Neurally Mediated Hypotension. The incidence, prevalence, and natural history of these conditions remain unquantified, but observations from specialist clinics suggest they are frequently seen in hEDS. There is growing understanding of how hEDS-related physical and physiological pathology contributes to the development of these conditions. Evaluation of cardiovascular symptoms in hEDS should include a careful history and clinical examination. Tests of cardiovascular function range from clinic room observation to tilt-table assessment to other laboratory investigations such as supine and standing catecholamine levels. Non-pharmacologic treatments include education, managing the environment to reduce exposure to triggers, improving cardiovascular fitness, and maintaining hydration. Although there are limited clinical trials, the response to drug treatments in hEDS is supported by evidence from case and cohort observational data, and short-term physiological studies. Pharmacologic therapy is indicated for patients with moderate-severe impairment of daily function and who have inadequate response or tolerance to conservative treatment. Treatment in hEDS often requires a focus on functional maintenance. Also, the negative impact of cardiovascular symptoms on physical and psycho-social well-being may generate a need for a more general evaluation and on-going management and support. © 2017 Wiley Periodicals, Inc.

Background People with the Ehlers-Danlos Syndromes (EDS), a group of heritable disorders of connective tissue, often report experiencing dental procedure pain despite local anesthetic (LA) use. Clinicians have been uncertain how to interpret this apparent LA resistance, as comparison of EDS and non-EDS patient experience is limited to anecdotal evidence and small case series. The primary goal of this hypothesis-generating study was to investigate the recalled adequacy of pain prevention with LA administered during dental procedures in a large cohort of people with and without EDS. A secondary exploratory aim asked people with EDS to recall comparative LA experiences. Methods We administered an online survey through various social media platforms to people with EDS and their friends without EDS, asking about past dental procedures, LA exposures, and the adequacy of procedure pain prevention. Among EDS respondents who both received LA and recalled the specific LA used, we compared agent-specific pain prevention for lidocaine, procaine, bupivacaine, mepivacaine, and articaine. Results Among the 980 EDS respondents who had undergone a dental procedure LA, 88% (n = 860) recalled inadequate pain prevention. Among 249 non EDS respondents only 33% (n = 83) recalled inadequate pain prevention (P < 0.001 compared to EDS respondents). The agent with the highest EDS-respondent reported success rate was articaine (30%), followed by bupivacaine (25%), and mepivacaine (22%). Conclusions EDS survey respondents reported nearly three times the rate of LA non-response compared to non-EDS respondents, suggesting that LAs were less effective in preventing their pain associated with routine office dental procedures.

ObjectiveThere is a pressing need to develop reliable molecular biomarkers in osteoarthritis. The aim of the study was to identify novel serum biomarkers for osteoarthritis using a metabolomics approach.MethodsA two-stage study design was utilised. 123 knee osteoarthritis cases and 299 controls were selected from the TwinsUK cohort as a discovery sample. 76 knee osteoarthritis cases and 100 controls from the Chingford Study were used as replication. Knee osteoarthritis was defined as either radiographic, medically diagnosed or total knee joint replacement due to primary osteoarthritis. All the subjects were unrelated white women. Their serum samples were assessed for targeted metabolite profiling by electrospray ionisation tandem mass spectrometry using the AbsoluteIDQ kit. 163 serum metabolites were assessed and their concentrations obtained. The ratios of metabolite concentrations as proxies for enzymatic reaction rates were calculated and tested for the association with knee osteoarthritis. Significance was assessed after adjustment for multiple testing (Bonferroni method) and potential confounders.ResultsIn the discovery stage, the authors identified 14 ratios significantly associated with knee osteoarthritis with p≤1.9×10−6. Two of these 14 ratios were successfully confirmed in the replication stage—the ratios of valine to histidine and xleucine to histidine, with p=0.002. The significance remained after adjustment for age and body mass index.ConclusionThis is the first serum-based metabolomic study of osteoarthritis in humans. The branched-chain amino acids to histidine ratio has potential clinical use as an osteoarthritis biomarker and shows the clinical potential of metabolomics.

Background A 73-year-old, previously well woman was admitted to an emergency department because of a 3-month history of severe proximal girdle pain and stiffness with loss of appetite and weight. She was referred to a rheumatologist 10 days after her initial presentation. Within 4 weeks she presented to an outpatient clinic with nausea, vomiting, shortness of breath, painful mouth ulcers, rash on her legs and a further decline in appetite; she was readmitted to hospital. Within 4 months of initial presentation she became jaundiced. Investigations At initial presentation, physical examination, biochemical, hematological and autoimmune screening, radiography of the pelvis, an abdominal ultrasound, and electromyography were conducted. At referral to a rheumatologist similar tests were repeated. At presentation to the outpatient clinic, hematological and biochemical screening, and a urine dipstick test were conducted. At readmittance to hospital, infectious and autoimmune screening, radiography of the chest, electrocardiogram, ultrasound of the abdomen, and renal biopsy were conducted. At the time of development of jaundice, biochemical and hematological screening, CT of the abdomen and ultrasound-guided biopsy of a pancreatic mass were conducted. Diagnosis Polymyalgia rheumatica, antineutrophil-cytoplasmic-antibody-positive microscopic polyangiitis with renal involvement and B-cell lymphoma of the head of the pancreas. Management The patient received oral prednisolone 15 mg daily for polymyalgia rheumatica along with alendronate 70 mg weekly. The patient received intravenous cyclophosphamide 500 mg and methylprednisolone 500 mg every 2 weeks for her microscopic polyangiitis with renal involvement. For B-cell lymphoma of the head of the pancreas, the patient received cyclophosphamide, doxorubicin, vincristine and prednisolone once monthly.

Summary Background Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. Methods We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z -score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Findings Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10 −109 for rs2282679, in GC ); 11q12 (p=2·1×10 −27 for rs12785878, near DHCR7 ); and 11p15 (p=3·3×10 −20 for rs10741657, near CYP2R1 ). Variants at an additional locus (20q13, CYP24A1 ) were genome-wide significant in the pooled sample (p=6·0×10 −10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10 −48 ) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10 −26 ) compared with those in the lowest quartile. Interpretation Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Funding Full funding sources listed at end of paper (see Acknowledgments).

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.

The importance of changing patterns of obesity in society and its implications for public health are well recognized. However, the adult life course of body mass index (BMI) changes in individuals over time is largely unknown and has mostly been extrapolated from cross-sectional studies. The present study examines individual specific variation of BMI during a 15-year follow-up period in a community-based sample of UK females. We attempted to establish whether there is a common, generalized pattern which captures variation in BMI over time. The participants of this study belong to a prospective population cohort of British women studied intensively since 1989: the Chingford Study. The sample originally consisted of 1,003 women aged 45–68 years, who were assessed annually for BMI during follow-up period. Polynomial regression models were used to assess longitudinal BMI variation. We observed a great stability in individual BMI variation during the follow-up period, reflected by high correlations between the baseline BMI and follow-up BMI 10 and 15 years later (r = 0.876, N = 810, and r = 0.824, N = 638, respectively). We also found that three different major age-related patterns in BMI could be clearly identified: no change in 30.6% in 58% it increased and in 11.4% it decreased with age. Thus, our data suggest that individual age-related changes in BMI are very different. Therefore, simply combining all individuals into groups by any other criteria (age, sex, etc.) and overlooking the distinctive patterns of BMI change may lead to biased inferences in epidemiologic and etiologic research of the future.

The murine arachidonate 15-lipoxygenase gene (Alox15) has recently been identified as a negative regulator of peak bone mineral density (BMD). The human ALOX15 gene shares significant sequence homology with the murine Alox15 gene; however, the human arachidonate 12-lipoxygenase gene (ALOX12) is functionally more similar to the mouse gene. Multiple single-nucleotide polymorphisms (SNPs) in the human ALOX15 and ALOX12 genes have previously been reported to be significantly associated with BMD in humans. On the basis of these data, we carried out our own investigation of the human ALOX15 and ALOX12 genes and their relationship with hip and spine BMD parameters. The study population consisted of 779 postmenopausal women with a mean (+/- standard deviation) age of 62.5 +/- 5.9 years at BMD measurement and was recruited from a single large general practice in Chingford, northeast London. Three SNPs from ALOX15 and five from ALOX12 were analyzed. None of the SNPs that we analyzed in ALOX15 were significantly associated with any of the BMD parameters or fracture data. However, we found that three SNPs from ALOX12, all previously associated with spine BMD in women, were significantly associated with spine and various hip BMD parameters in our cohort (P = 0.029-0.049). In conclusion, we found no association between polymorphism in ALOX15 and BMD phenotypes but were able to replicate previous findings that genetic variation in ALOX12 seems to play a role in determining bone structure in Caucasian women.

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].

A unique guide which emphasizes a clinical, evidence-based approach to rheumatology. The resource provides practical guidelines to the management and diagnosis of patients with acute and chronic musculoskeletal disease.

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.

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.