Low tendon stiffness and abnormal ultrastructure distinguish classic Ehlers-Danlos syndrome from benign joint hypermobility syndrome in patients.

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.

Lack of consensus on tests and criteria for generalized joint hypermobility, Ehlers-Danlos syndrome: hypermobile type and joint hypermobility syndrome.

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.

Generalized joint hypermobility in childhood is a possible risk for the development of joint pain in adolescence: a cohort study.

BACKGROUND: 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. METHODS: This was a longitudinal cohort study nested within the Copenhagen Hypermobility Cohort. All children (n = 301) were examined for the exposure, GJH, using the Beighton test at baseline at either 8 or 10 years of age and then re-examined when they reached 14 years of age. The children were categorized into two groups based on their number of positive Beighton tests using different cut points (i.e. GJH4 defined as either < 4 or ≥ 4, GJH5 and GJH6 were similarly defined). The outcome of joint pain was defined as arthralgia as measured by the Brighton criteria from the clinical examination. Other outcome measures of self-reported physical function and objective physical function were also collected. RESULTS: Children with GJH had three times higher risk of developing joint pain in adolescence, although this association did not reach statistical significance (GJH5: 3.00, 95% [0.94-9.60]). At age 14, the adolescents with GJH had significantly lower self-reported physical function (for ADL: GJH4 p = 0.002, GJH5 p = 0.012; for pain during sitting: GJH4 p = 0.002, GJH5 p = 0.018) and had significantly higher body mass index (BMI: GJH5 p = 0.004, GJH6 p = 0.006) than adolescents without GJH. There was no difference in measured physical function. CONCLUSION: This study has suggested a possible link between GJH and joint pain in the adolescent population. GJH was both a predictive and a contributing factor for future pain. Additional studies with larger sample sizes are needed to confirm our findings.

Effect of generalized joint hypermobility on knee function and muscle activation in children and adults.

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.

Gait pattern in 9-11-year-old children with generalized joint hypermobility compared with controls; a cross-sectional study.

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).

Inter-examiner reproducibility of tests for lumbar motor control.

BACKGROUND: Many studies show a relation between reduced lumbar motor control (LMC) and low back pain (LBP). However, test circumstances vary and during test performance, subjects may change position. In other words, the reliability--i.e. reproducibility and validity--of tests for LMC should be based on quantitative data. This has not been considered before. The aim was to analyse the reproducibility of five different quantitative tests for LMC commonly used in daily clinical practice. METHODS: The five tests for LMC were: repositioning (RPS), sitting forward lean (SFL), sitting knee extension (SKE), and bent knee fall out (BKFO), all measured in cm, and leg lowering (LL), measured in mm Hg. A total of 40 subjects (14 males, 26 females) 25 with and 15 without LBP, with a mean age of 46.5 years (SD 14.8), were examined independently and in random order by two examiners on the same day. LBP subjects were recruited from three physiotherapy clinics with a connection to the clinic's gym or back-school. Non-LBP subjects were recruited from the clinic's staff acquaintances, and from patients without LBP. RESULTS: The means and standard deviations for each of the tests were 0.36 (0.27) cm for RPS, 1.01 (0.62) cm for SFL, 0.40 (0.29) cm for SKE, 1.07 (0.52) cm for BKFO, and 32.9 (7.1) mm Hg for LL. All five tests for LMC had reproducibility with the following ICCs: 0.90 for RPS, 0.96 for SFL, 0.96 for SKE, 0.94 for BKFO, and 0.98 for LL. Bland and Altman plots showed that most of the differences between examiners A and B were less than 0.20 cm. CONCLUSION: These five tests for LMC displayed excellent reproducibility. However, the diagnostic accuracy of these tests needs to be addressed in larger cohorts of subjects, establishing values for the normal population. Also cut-points between subjects with and without LBP must be determined, taking into account age, level of activity, degree of impairment and participation in sports. Whether reproducibility of these tests is as good in daily clinical practice when used by untrained examiners also needs to be examined.

Skeletal muscle morphology, protein synthesis, and gene expression in Ehlers-Danlos syndrome.

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.

Tendon protein synthesis rate in classic Ehlers-Danlos patients can be stimulated with insulin-like growth factor-I.

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.

Gait analysis of adults with generalised joint hypermobility.

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.

Knee function in 10-year-old children and adults with Generalised Joint Hypermobility.

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 (100mm VAS), Knee injury and Osteoarthritis Outcome Score (KOOS) (only adults), measured maximum isokinetic knee strength (60°/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.

Scapular dyskinesis in trapezius myalgia and intraexaminer reproducibility of clinical tests.

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.

Motor competence and physical activity in 8-year-old school children with generalized joint hypermobility.

OBJECTIVE: Because the criteria used for diagnosing between generalized joint hypermobility (GJH) and musculoskeletal complaints, as well as relations between GJH and an insufficient motor development and/or a reduced physical activity level differ, the prevalence of GJH varies considerably. The aim of this study was to survey the prevalence of GJH defined by a Beighton score at >or=4, >or=5, or >or=6 positive tests of 9 and benign joint hypermobility syndrome (BJHS) in Danish primary school children at 8 years of age. A second aim was to compare children with and without GJH and BJHS regarding motor competence, self-reported physical activity, and incidence of musculoskeletal pain and injuries. METHODS: A cross-sectional study of 524 children in the second grade from 10 public schools was performed. A positive response rate was obtained for 416 (79.4%) children, and 411 (78.4%) children were clinically examined and tested for motor competence, whereas questionnaire response to items comprising musculoskeletal pain and injuries, in addition to daily level and duration of physical activity, corresponded to 377 (71.9%) children. RESULTS: In total, 29% of the children had GJH4, 19% had GJH5, 10% had GJH6, and 9% had BJHS, with no gender difference. There was no difference in daily level and duration of physical activity and in frequency of musculoskeletal pain and injuries between those with and without GJH. Children with >or=GJH5 as well as with >or=GJH6 performed better in the motor competence tests. CONCLUSION: Motor competence and physical activity are not reduced in primary school children at 8 years of age with GJH or BJHS. It is recommended that a potential negative influence on the musculoskeletal system over time, as a result of GJH, be investigated by longitudinal studies.

Are diagnostic criteria for general joint hypermobility and benign joint hypermobility syndrome based on reproducible and valid tests? A review of the literature.

OBJECTIVE: In this review we focus on current knowledge of the reliability of tests and diagnostic criteria for generalized joint hypermobility (GJH) and benign joint hypermobility syndrome (BJHS). METHODS: Currently, The British Society of Rheumatology recommends the Beighton scoring system. With this approach, GJH is judged present when 4 or more of 9 tests are positive. Curiously, only one inter/intrarater reproducibility study is available and it uses a cutoff level of 6, rather than the Beighton-recommended 4 positive tests. RESULTS: Using a 6 cut level, intra- and interobserver kappa scores were 0.75 and 0.78, respectively. Beighton scoring recommendations have been correlated with a global joint mobility index as well as with 2 other scoring systems, the Carter and Wilkinson, and the Rotès-Quérol. All illustrate high concurrent validity with one another. For the recently proposed Brighton criteria diagnosing BJHS no reproducibility studies exist. In the latter, the recommendations reflect high nosographic sensitivity and specificity while predictive values for positive test scores are poor. CONCLUSION: In general, the reproducibility of the various tests seems to be good, especially when performed by experienced rheumatologists.

Epidemiology of general joint hypermobility and basis for the proposed criteria for benign joint hypermobility syndrome: review of the literature.

OBJECTIVE: This literature review of generalized joint hypermobility (GJH) syndromes discusses information regarding sex-, age-, and race-related factors from publications that specifically document validated GJH criteria. METHODS: We present an analysis of criterion-referenced connections that identify similarities among major and minor clinical criteria that identify both GJH and benign joint hypermobility syndrome (BJHS). In our search, we found considerable empirical evidence that supports an increased prevalence of hypermobility among children, women, and certain racial groups. Two commonly used clinical assessment tools, the Carter and Wilkinson criteria (>or= 3 positive tests out of 5) and the Beighton method (>or= 4 positive tests out of 9), are the sources of these data. BJHS is diagnosed through a set of major and minor criteria - a combination of symptoms and objective findings -- that include arthralgia, back pain, spondylosis, spondylolysis/spondylolisthesis, joint dislocation/subluxation, soft tissue rheumatism, marfanoid habitus, abnormal skin, eye signs, varicose veins or hernia or uterine/rectal prolapse. RESULTS: Clinically, there is some evidence that arthralgia, the proposed BJHS major criterion, is a major component of alleged hypermobility-related problems. In contrasting, there is no clear evidence that proposed BJHS minor diagnostic criteria are associated with hypermobility-related problems. An empirical correlation between hypermobility and osteoarthritis is possible, but so far unproven. There are no randomized controlled studies regarding effects of existing treatments. CONCLUSION: Generalized hypermobility is both sex- and age-related. Racial differences are also identifiable. The existence of BJHS can be accepted using present criteria.

[Generalised joint hypermobility and benign joint hypermobility syndrome. I: reproducibility and validity of tests and criteria]. / Hypermobilitas articulorum og hypermobilitetssyndrom. I: reproducerbarhed og validitet af test og kriterier.

The clinician's evaluation of the presence of joint hypermobility is most often performed through application of a joint mobility scoring system. Several systems are available, all of them based on tests of selected joints or movements. In most cases, a positive test is based on a range of motion at or above the mean range of motion +3 SD. The tests' reproducibility is good when performed by an experienced rheumatologist; however, their validity is unknown as there are no gold standards. The British Society of Rheumatology has recommended Beighton's scoring system and the level > or =4 positive tests out of 9 as the criterion for general hypermobility. The reproducibility of the criterion has been examined only once, and only with the cut level of > or =6/9 tests. At this level, the intra- and interobserver variability was 0.75 and 0.78, respectively. In another study it was demonstrated that the Beighton scoring system correlates well with a global joint mobility index and shows good agreement with two other scoring systems. The diagnostic specificity is poor with regard to the criteria for benign joint hypermobility syndrome.

[Generalised joint hypermobility and benign joint hypermobility syndrome. II: epidemiology and clinical criteria]. / Hypermobilitas articulorum og hypermobilitetssyndrom. II: epidemiologi og klinik.

Gender-, age- and race-related generalised joint hypermobility (GJH) is elucidated, based on publications that have used validated criteria for GJH. Furthermore, we analysed the connection between GJH and the clinical criteria for benign joint hypermobility syndrome (BJHS), and we looked for literature on the treatment of BJHS. There seems to be evidence in support of an increased prevalence of hypermobility among children, females and certain races when the diagnosis of hypermobility is based on the Carter and Wilkinson criteria (> or =3 positive tests out of 5) and/or Beighton's tests (> or =4 positive tests out of 9). However, there are no unequivocal statements that hypermobility predisposes to the various clinical situations used as major or minor criteria for BJHS, e.g., arthralgia, low back and pelvic pain, joint luxation, soft tissue rheumatism, abnormal cutis or genitourinary prolapse, varicose veins and hernia. There have been no randomised controlled studies of the effect of treatment.