Patients with Ehlers-Danlos syndrome (EDS) are known to have genetically impaired connective tissue and skeletal muscle symptoms in form of pain, fatigue, and cramps; however earlier studies have not been able to link these symptoms to morphological muscle changes. We obtained skeletal muscle biopsies in patients with classic EDS [cEDS; n = 5 (Denmark)+ 8 (The Netherlands)] and vascular EDS (vEDS; n = 3) and analyzed muscle fiber morphology and content (Western blotting and muscle fiber type/area distributions) and muscle mRNA expression and protein synthesis rate (RT-PCR and stable isotope technique). The cEDS patients did not differ from healthy controls (n = 7-11) with regard to muscle fiber type/area, myosin/α-actin ratio, muscle protein synthesis rate, or mRNA expression. In contrast, the vEDS patients demonstrated higher expression of matrix proteins compared with cEDS patients (fibronectin and MMP-2). The cEDS patients had surprisingly normal muscle morphology and protein synthesis, whereas vEDS patients demonstrated higher mRNA expression for extracellular matrix remodeling in skeletal musculature compared with cEDS patients.NEW & NOTEWORTHY This study is the first of its kind to systematically investigate muscle biopsies from Ehlers-Danlos patients, focusing on muscle structure and function. These patients suffer from severe muscle symptoms, but in our study they show surprisingly normal muscle findings, which points toward indirect muscle symptoms originating from the surrounding connective tissue. These findings have basal physiological importance and implications for future physiotherapeutic treatment options for these patients.

The classic form of Ehlers-Danlos syndrome (cEDS) is an inherited connective tissue disorder, where mutations in type V collagen-encoding genes result in abnormal collagen fibrils. Thus the cEDS patients have pathological connective tissue morphology and low stiffness, but the rate of connective tissue protein turnover is unknown. We investigated whether cEDS affected the protein synthesis rate in skin and tendon, and whether this could be stimulated in tendon tissue with insulin-like growth factor-I (IGF-I). Five patients with cEDS and 10 healthy, matched controls (CTRL) were included. One patellar tendon of each participant was injected with 0.1 ml IGF-I (Increlex, Ipsen, 10 mg/ml) and the contralateral tendon with 0.1 ml isotonic saline as control. The injections were performed at both 24 and 6 h prior to tissue sampling. The fractional synthesis rate (FSR) of proteins in skin and tendon was measured with the stable isotope technique using a flood-primed continuous infusion over 6 h. After the infusion one skin biopsy and two tendon biopsies (one from each patellar tendon) were obtained. We found similar baseline FSR values in skin and tendon in the cEDS patients and controls [skin: 0.005 ± 0.002 (cEDS) and 0.007 ± 0.002 (CTRL); tendon: 0.008 ± 0.001 (cEDS) and 0.009 ± 0.002 (CTRL) %/h, mean ± SE]. IGF-I injections significantly increased FSR values in cEDS patients but not in controls (delta values: cEDS 0.007 ± 0.002, CTRL 0.001 ± 0.001%/h). In conclusion, baseline protein synthesis rates in connective tissue appeared normal in cEDS patients, and the patients responded with an increased tendon protein synthesis rate to IGF-I injections.

The objectives of this study were to register clinicians performance and opinion of importance of clinical tests for generalized joint hypermobility (GJH), Ehlers–Danlos syndrome, hypermobility type (EDS‐HT) and joint hypermobility syndrome (JHS), and to reach a consensus among clinicians on criteria for diagnosing GJH, EDS‐HT and JHS. A panel of clinicians answered questions about how to perform and interpret clinical tests and rated test importance on an 11‐box scale. The questionnaire was developed on the basis of information from focus groups and the literature. Cronbach's α was used as a measure of internal consistency/consensus among the panelists. The results showed Cronbach's α on importance score of items for diagnosing GJH, EDS‐HT and JHS was 0.61, 0.79, and 0.44, respectively. Panelist‐group correlation for the three conditions varied substantially (−0.46 to 0.89, 0.03 to 0.68, and −0.07 to 0.68) indicating heterogeneity among the panelists. There was agreement on which tests to use, but performance of the tests (i.e., the specific maneuvers) varied considerably inclusive use of tests with unknown reliability. Furthermore, agreement on the diagnostic criteria varied. We conclude that the level of consensus for the importance of various items for diagnosing GJH, EDS‐HT and JHS, was below the required limit (Cronbach's α >0.90) for clinical decision‐making and diagnosing. Consensus on tests and criteria through a Delphi process could not be reached. Better descriptions of, and reliability studies on, test maneuvers and criteria sets for these conditions are needed. Subsequent intensive training and implementation of these tests and criteria, nationally as well as internationally should be established. © 2014 Wiley Periodicals, Inc.

There is a clinical overlap between classic Ehlers-Danlos syndrome (cEDS) and benign joint hypermobility syndrome (BJHS), with hypermobility as the main symptom. The purpose of this study was to investigate the role of type V collagen mutations and tendon pathology in these 2 syndromes. In patients (cEDS, n=7; BJHS, n=8) and controls (Ctrl, n=8), we measured patellar tendon ultrastructure (transmission electron microscopy), dimensions (magnetic resonance imaging), and biomechanical properties (force and ultrasonographic measurements during a ramped isometric knee extension). Mutation analyses (COL5A1 and COL5A2) were performed in the patients. COL5A1 mutations were found in 3 of 4 of the patients with cEDS. Patellar tendon dimensions were similar between the groups, but large, irregular collagen fibrils were in 4 of 5 patients with cEDS. In the cEDS group, tendon stiffness and Young's modulus were reduced to ∼50% of that in BJHS and Ctrl groups (P<0.05). The nonhypermobile, healthy controls were matched with the patients in age, sex, body weight, and physical activity, to compare outcomes. COL5A1 mutations led to structural tendon pathology and low tendon stiffness in cEDS, explaining the patients' hypermobility, whereas no tendon pathology was found that explained the hypermobility in BJHS.

There is some evidence that indicates generalized joint hypermobility (GJH) is a risk factor for pain persistence and recurrence in adolescence. However, how early pain develops and whether GJH without pain in childhood is a risk factor for pain development in adolescence is undetermined. The aims for this study were to investigate the association between GJH and development of joint pain and to investigate the current GJH status and physical function in Danish adolescents.

INTRODUCTION:We investigated muscle activation strategy and performance of knee extensor and flexor muscles in children and adults with generalized joint hypermobility (GJH) and compared them with controls.METHODS:Muscle activation, torque steadiness, electromechanical delay, and muscle strength were evaluated in 39 children and 36 adults during isometric knee extension and flexion. Subjects performed isometric maximum contractions, submaximal contractions at 25% maximum voluntary contraction (MVC), and explosive contractions.RESULTS:Agonist activation was reduced, and coactivation ratio was greater in GJH during knee flexion compared with controls. Torque steadiness was impaired in adults with GJH during knee flexion. No effect of GJH was found on muscle strength or electromechanical delay. Correlation analysis revealed an association between GJH severity and function in adults.CONCLUSIONS:The results indicate that muscle activation strategy and quality of force control were significantly affected in adults with GJH during knee flexion, whereas only muscle activation strategy was affected in children with GJH.

BACKGROUND:To study differences in gait patterns in 10-year-old children with Generalized Joint Hypermobility (GJH) and with no GJH (NGJH).METHODS:A total of 37 children participated (19 GJH, 18 NGJH, mean age 10.2 (SD 0.5) years). Inclusion criteria for GJH were a Beighton score of ≥5, with at least one hypermobile knee joint; for NGJH a Beighton score of ≤4, and no hypermobile knees and for both groups no knee pain during the previous week. All children were recorded by five video cameras, while they walked across three force platforms. Net joint moments were calculated in 3D by inverse dynamics and peak values provided input to statistical analyses.RESULTS:In the frontal plane, children with GJH had a significantly lower peak knee abductor moment and peak hip abductor moment. In the sagittal plane, the peak knee flexor moment and the peak hip extensor moment were significantly lower in the GJH group although the absolute difference was small.CONCLUSIONS:The walking pattern was the same for children with GJH and for healthy children, as there were no differences in kinematics, but it was, however, performed with different kinetics. Children with GJH walked with lower ankle, knee and hip joint moments compared to children with NGJH. However, the clinical importance of these differences during normal gait is unknown. To obtain this knowledge, children with GJH must be followed longitudinally.TRIAL REGISTRATION:The study was approved by the Committee on Biomedical Research Ethics for Copenhagen and Frederiksberg, Denmark (jnr. KF01-2006-178).

BACKGROUND:The purpose of the study was to investigate if differences of the head and trunk stability and stabilization strategies exist between subjects classified with Generalized Joint Hypermobility and healthy controls during gait. It was hypothesized that joint hypermobility could lead to decreased head and trunk stability and a head stabilization strategy similar to what have been observed in individuals with decreased locomotor performance.METHODS:A comparative study design was used wherein 19 hypermobile children were compared to 19 control children, and 18 hypermobile adults were compared to 18 control adults. The subjects were tested during normal walking and walking on a line. Kinematics of head, shoulder, spine and pelvis rotations were measured by five digital video cameras in order to assess the segmental stability (angular dispersion) and stabilization strategies (anchoring index) in two rotational components: roll and yaw.FINDINGS:Hypermobile children and adults showed decreased lateral trunk stability in both walking conditions. In hypermobile children, it was accompanied with decreased head stability as the head was stabilized by the inferior segment when walking on a line. Several additional differences were observed in stability and stabilization strategies for both children and adults.INTERPRETATION:Stability of the trunk was decreased in hypermobile children and adults. This may be a consequence of decreased stability of the head. Hypermobile children showed a different mode of head stabilization during more demanding locomotor conditions indicating delayed locomotor development. The findings reflect that Generalized Joint Hypermobility probably include motor control deficits.

There are no precise prevalence rates of adults with generalised joint hypermobility (GJH), and in a recent review the prevalence for adults varies from 2% to 57% depending on age, gender and ethnic origin. For children the prevalence varies from 7% to 36%, primarily depending on the tests and criteria (especially the cut-off points) used for diagnosing GJH.

Classic Ehlers‐Danlos Syndrome (cEDS) is mainly caused by collagen V mutations and the phenotype is associated with joint hypermobility, pain and dislocations. Eight patients clinically diagnosed with cEDS (age 39 ± 11 years, BMI 24 ± 4 kg/m2, mean ± SD) were matched with eight healthy controls (age 41 ± 14 years, BMI 25 ± 5 kg/m2). Patellar tendon tissue was imaged with transmission electron microscopy (TEM), tendon size was obtained with magnetic resonance imaging (MRI) and measures of tendon biomechanical properties were done by ultrasonography‐based tendon elongation during isometric knee contractions. TEM images revealed large irregular collagen fibrils (cauliflower‐like) in cEDS patients. MRI showed no differences in tendon size between cEDS and controls. The biomechanical properties of the patellar tendon were severely altered in cEDS patients; showing >;60% reduction in stiffness (1486 ± 698 vs. 4029 ± 1645 N/mm, p<0.01) and Young's modulus (0.56 ± 0.29 vs. 1.68 ± 0.75 GPa, p<0.05) compared to controls. In conclusion, the altered tendon ultrastructure and stiffness in cEDS patients indicate that tendon tissue can, at least partly, explain the observed joint hypermobility in cEDS.

Introduction . To provide a state of the art on diagnostics, clinical characteristics, and treatment of paediatric generalised joint hypermobility (GJH) and joint hypermobility syndrome (JHS). Method . A narrative review was performed regarding diagnostics and clinical characteristics. Effectiveness of treatment was evaluated by systematic review. Searches of Medline and Central were performed and included nonsymptomatic and symptomatic forms of GJH (JHS, collagen diseases). Results . In the last decade, scientific research has accumulated on all domains of the ICF. GJH/JHS can be considered as a clinical entity, which can have serious effects during all stages of life. However research regarding the pathological mechanism has resulted in new potential opportunities for treatment. When regarding the effectiveness of current treatments, the search identified 1318 studies, from which three were included (JHS:n=2, Osteogenesis Imperfecta:n=1). According to the best evidence synthesis, there was strong evidence that enhancing physical fitness is an effective treatment for children with JHS. However this was based on only two studies. Conclusion . Based on the sparsely available knowledge on intervention studies, future longitudinal studies should focus on the effect of physical activity, fitness, and joint stabilisation. In JHS and chronic pain, the effectiveness of a multidisciplinary approach should be investigated.

Background The majority of adults with Generalised Joint Hypermobility experience symptoms such as pain and joint instability, which is likely to influence their gait pattern. Accordingly, the purpose of the present project was to perform a biomechanical gait analysis on a group of patients with Generalised Joint Hypermobility and compare them to a group of healthy subjects. Methods Seventeen adults clinically classified with Generalised Joint Hypermobility (6 males and 11 females) and seventeen healthy subjects (9 males and 8 females) were included in the project. The subjects walked across three force platforms while they were filmed by five video cameras. Net joint moments were calculated in 3D by inverse dynamics and peak values were input to statistical analyses. A 3D knee joint model was used to calculate bone-on-bone forces. Findings In the frontal plane both the peak knee and hip abductor moments were 13% higher in the patient group. In the sagittal plane the peak knee extensor moment was 10% higher for the patients and the flexor moment about the knee joint in the middle of stance was 27% lower for the patients. Increased flexion in the knee joint for the patients was also observed. Interpretation The finding that adults with Generalised Joint Hypermobility display higher joint moments during walking in both the frontal and the sagittal planes and increased knee joint loadings may explain the pain symptoms in the patient group and indicate these subjects are subjected to an increased risk of developing osteo-arthritis.

Purpose: Knee function is reduced in patients with Benign Joint Hypermobility Syndrome. The aim was to study knee function in children and adults with Generalised Joint Hypermobility (GJH) and Non-GJH (NGJH)).Materials and methods: In a matched comparative study, 39 children and 36 adults (mean age children 10.2 years; adults 40.3 years) were included, comprising 19 children and 18 adults with GJH (Beighton >= 5/9; Beighton >= 4/9), minimum one hypermobile knee, no knee pain (children), and 20 children and 18 adults with NGJH (Beighton <5; Beighton <4). Totally, 85% of the adults were parents to these children.Knee function was determined by self-reported physical fitness (100 mm VAS), Knee injury and Osteoarthritis Outcome Score (KOOS) (only adults), measured maximum isokinetic knee strength (60 degrees/s) and peak vertical jump displacement (PVJD), with calculated knee strength balance, Hamstring/Quadriceps (H/Q) ratio and peak rate of force development (PRFD).Results: Adults with GJH had lower knee function (KOOS: pain, p = 0.001; symptoms, p = 0.001; Activities of Daily Living, p = 0.001; Sport/Recreation, p = 0.003; knee-related quality of life, p<0.001), and H/Q ratio (0.46 vs. 0.54, p = 0.046) than adults with NGJH, regardless of age and knee pain. Both GJH groups had normal physical fitness, isokinetic knee strength, and (only children) H/Q ratio.Conclusions: Children at 10 years with GJH have normal, but adults with GJH have impaired knee function. To track the risk of developing impaired knee function, children with GJH must be followed longitudinally. Meanwhile, attention to knee function may be given to children with GJH who have parents presenting GJH. (C) 2012 Elsevier B.V. All rights reserved.

Britta Berglund, Antonio Bulbena, Peter H. Byers, Rodney Grahame, Birgit JuulKristensen, Karl-August Lindgren, Jouni Uitto and Lena L. Wekre Department of Rheumatology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark, University of Applied Sciences, Amsterdam School of Health Professions, Amsterdam, The Netherlands, Nursing Division, CLINTEC, Karolinska University Hospital, Stockholm, Sweden, Institute of Psychiatry, Autonomous University of Barcelona, Barcelona, Spain, Departments of Pathology and Medicine (Medical Genetics), University of Washington, Seattle, WA, USA, University College Hospital, London, UK, Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark, Rehab ORTON, Helsinki, Finland, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA and TRS Centre, Sunnaas, Oslo, Norway. Accepted 9 March 2011 Correspondence to: Lars Remvig, Department of Rheumatology, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. E-mail: lars.remvig@rh.regionh.dk

The aims were to test the intraexaminer reproducibility and report the presence of specific clinical variables of scapular dyskinesis in cases with trapezius myalgia and healthy controls, along with general health and work ability. A total of 38 cases and 23 controls were tested for scapular dyskinesis, general health, and work ability, and 19 cases and 14 controls participated in the reproducibility study. Intraexaminer reproducibility was good to excellent for 6 of 10 clinical variables (Intraclass Correlation Coefficient [ICC] 0.76–0.91; kappa 0.84–1.00), and fair to good for four variables (ICC 0.42–0.74), test for muscular weakness having the lowest ICC (0.42). Cases showed significantly larger medial border misalignment, larger lower horizontal distance of the inferior scapular angle and larger passive shoulder internal rotation, by 110% (1.02 cm), 15% (1.38 cm), and 8% (5.5°), respectively. Cases with the highest degree of scapular dyskinesis showed reduced work ability and general health. The present specific clinical variables on scapular dyskinesis showed satisfactory intraexaminer reproducibility. An increased standardization must be implemented to increase reproducibility of tests for muscular weakness, and the interexaminer reproducibility must be tested for all variables. Finally, scapular dyskinesis in cases with trapezius myalgia must be followed longitudinally for clinical importance.