Physical fitness in children with Marfan and Loeys-Dietz syndrome: associations between cardiovascular parameters, systemic manifestations, fatigue, and pain.

Children with Marfan (MFS) and Loeys-Dietz syndrome (LDS) report limitations in physical activities, sports, school, leisure, and work participation in daily life. This observational, cross-sectional, multicenter study explores associations between physical fitness and cardiovascular parameters, systemic manifestations, fatigue, and pain in children with MFS and LDS. Forty-two participants, aged 6-18 years (mean (SD) 11.5(3.7)), diagnosed with MFS (n = 36) or LDS (n = 6), were enrolled. Physical fitness was evaluated using the Fitkids Treadmill Test's time to exhaustion (TTE) outcome measure. Cardiovascular parameters (e.g., echocardiographic parameters, aortic surgery, cardiovascular medication) and systemic manifestations (systemic score of the revised Ghent criteria) were collected. Pain was obtained by visual analog scale. Fatigue was evaluated by PROMIS® Fatigue-10a-Pediatric-v2.0-short-form and PROMIS® Fatigue-10a-Parent-Proxy-v2.0-short-form. Multivariate linear regression analyses explored associations between physical fitness (dependent variable) and independent variables that emerged from the univariate linear regression analyses (criterion p < .05). The total group (MFS and LDS) and the MFS subgroup scored below norms on physical fitness TTE Z-score (mean (SD) -3.1 (2.9); -3.0 (3.0), respectively). Univariate analyses showed associations between TTE Z-score aortic surgery, fatigue, and pain (criterion p < .05). Multivariate analyses showed an association between physical fitness and pediatric self-reported fatigue that explained 48%; 49%, respectively, of TTE Z-score variance (F (1,18) = 18.6, p ≤ .001, r2 = .48; F (1,15) = 16,3, p = .01, r2 = .49, respectively).    Conclusions: Physical fitness is low in children with MFS or LDS and associated with self-reported fatigue. Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with MFS and LDS. What is Known: • Marfan and Loeys-Dietz syndrome are heritable connective tissue disorders and share cardiovascular and systemic manifestations. • Children with Marfan and Loeys-Dietz syndrome report increased levels of disability, fatigue and pain, as well as reduced levels of physical activity, overall health and health-related quality of life. What is New: • Physical fitness is low in children with Marfan and Loeys-Dietz syndrome and associated with self-reported fatigue. • Our findings emphasize the potential of standardized and tailored exercise programs to improve physical fitness and reduce fatigue, ultimately enhancing the physical activity and sports, school, leisure, and work participation of children with Marfan and Loeys-Dietz syndrome.

Somatic symptoms, pain, catastrophizing and the association with disability among children with heritable connective tissue disorders.

The aim of the present study was to investigate the nature and prevalence of nonspecific somatic symptoms, pain and catastrophizing in children with Heritable Connective Tissue Disorders (HCTD), and to determine their association with disability. This observational, multicenter study included 127 children, aged 4-18 years, with Marfan syndrome (MFS) (59%), Loeys-Dietz syndrome (LDS) (8%), Ehlers-Danlos syndromes (EDS) (12%) and hypermobile Ehlers-Danlos syndrome (hEDS) (23%). The assessments included the Children's Somatization Inventory or parent proxy (CSI, PCSI), pain visual-analogue scale (VAS), SUPERKIDZ body diagram, Pain Catastrophizing Scale Child or parent proxy (PCS-C, PCS-P) and Childhood Health Assessment Questionnaire (CHAQ-30). Data from children aged ≥8 years were compared to normative data. In children ≥ 8 years (n = 90), pain was present in 59%, with a median of 4 (IQR = 3-9) pain areas. Compared to normative data, the HCTD group reported significantly higher on the CSI (p ≤ 0.001, d = 0.85), VAS pain intensity (p ≤ 0.001, d = 1.22) and CHAQ-30 (p ≤ 0.001, d = 1.16) and lower on the PCS-C (p = 0.017, d = -0.82) and PCS-P (p ≤ 0.001, d = -0.49). The intensity of nonspecific somatic symptoms and pain explained 45% of the variance in disability (r2 = 0.45 F(2,48) = 19.70, p ≤ 0.001). In children ≤ 7 years (n = 37), pain was present in 35% with a median of 5(IQR = 1-13) pain areas. The mean(SD) VAS scores for pain intensity was 1.5(2.9). Functional disability was moderately correlated to the number of pain areas (r = 0.56, p ≤ 0.001), intensity of nonspecific somatic symptoms (r = 0.63, p ≤ 0.001) and pain (r = 0.83, p ≤ 0.001). In conclusion, this study supports the need for comprehensive assessment of nonspecific somatic symptoms, pain, and disability in children with HCTD to allow tailored treatment.

Heritable connective tissue disorders in childhood: Decreased health-related quality of life and mental health.

The psychosocial consequences of growing up with Heritable Connective Tissue Disorders (HCTD) are largely unknown. We aimed to assess Health-Related Quality of Life (HRQoL) and mental health of children and adolescents with HCTD. This observational multicenter study included 126 children, aged 4-18 years, with Marfan syndrome (MFS, n = 74), Loeys-Dietz syndrome (n = 8), molecular confirmed Ehlers-Danlos syndromes (n = 15), and hypermobile Ehlers-Danlos syndrome (hEDS, n = 29). HRQoL and mental health were assessed through the parent and child-reported Child Health Questionnaires (CHQ-PF50 and CHQ-CF45, respectively) and the parent-reported Strengths and Difficulties Questionnaire. Compared with a representative general population sample, parent-reported HRQoL of the HCTD-group showed significantly decreased Physical sum scores (p < 0.001, d = 0.9) and Psychosocial sum scores (p = 0.024, d = 0.2), indicating decreased HRQoL. Similar findings were obtained for child-reported HRQoL. The parent-reported mental health of the HCTD-group showed significantly increased Total difficulties sum scores (p = 0.01, d = 0.3), indicating decreased mental health. While the male and female MFS- and hEDS-subgroups both reported decreased HRQoL, only the hEDS-subgroup reported decreased mental health. In conclusion, children and adolescents with HCTD report decreased HRQoL and mental health, with most adverse outcomes reported in children with hEDS and least in those with MFS. These findings call for systematic monitoring and tailored interventions.

Muscle Strength, Muscle Mass and Physical Impairment in Women with hypermobile Ehlers-Danlos syndrome and Hypermobility Spectrum Disorder.

OBJECTIVES: To evaluate differences in physical impairment, muscle strength, muscle mass and muscle density between patients with hypermobile Ehlers Danlos Syndrome (hEDS), hypermobile spectrum disorder (HSD), and healthy controls. METHODS: Female adults with hEDS (n=20) and HSD (n=23), diagnosed to the most recent criteria, and age-matched healthy controls (n=28) completed the Arthritis Impact Measurement Scale (physical functioning) and performed maximal muscle strength and strength endurance tests of lower and upper limbs (hand grip, posture maintenance, 30 seconds chair rise and isokinetic tests). Muscle mass and density were evaluated by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. RESULTS: No differences in physical functioning and muscle strength were found between adults with hEDS and HSD. Furthermore, no differences in muscle mass and density were observed between the three groups. Nevertheless, when both patient groups were compared to controls, physical functioning, maximal muscle strength and muscle strength endurance were significantly lower (all p<0.001), except for the hand flexors. CONCLUSION: Physical functioning, muscle strength, density and mass did not significantly differ between individuals with hEDS and HSD. Compared to controls, physical functioning and muscle strength (maximal and endurance) were significantly lower. Consequently, (functional) strength training in individuals with hEDS and HSD is necessary.

International Perspectives on Joint Hypermobility: A Synthesis of Current Science to Guide Clinical and Research Directions.

ABSTRACT: There is exponential clinical and research interest in joint hypermobility due to recognition of the complexity of identification, assessment, and its appropriate referral pathways, ultimately impacting management. This state-of-the-science review provides an international, multidisciplinary perspective on the presentation, etiology, and assessment of joint hypermobility, as it presents in those with and without a systemic condition. We synthesize the literature, propose standardizing the use of terminology and outcome measures, and suggest potential management directions. The major topics covered are (i) historical perspectives; (ii) current definitions of hypermobility, laxity, and instability; (iii) inheritance and acquisition of hypermobility; (iv) traditional and novel assessments; (v) strengths and limitations of current assessment tools; (vi) age, sex, and racial considerations; (vii) phenotypic presentations; (viii) generalized hypermobility spectrum disorder and hypermobility Ehlers-Danlos syndrome; and (ix) clinical implications and research directions. A thorough understanding of these topics will equip the reader seeking to manage individuals presenting with joint hypermobility, while mindful of its etiology. Management of generalized joint hypermobility in the context of a complex, multisystem condition will differ from that of acquired hypermobility commonly seen in performing artists, specific athletic populations, posttrauma, and so on. In addition, people with symptomatic hypermobility present predominantly with musculoskeletal symptoms and sometimes systemic symptoms including fatigue, orthostatic intolerance, and gastrointestinal or genitourinary issues. Some also display skeletal deformities, tissue and skin fragility, and structural vascular or cardiac differences, and these warrant further medical follow-up. This comprehensive review on the full spectrum of joint hypermobility will assist clinicians, coaches/sports trainers, educators, and/or researchers in this area.

Pain in the Ehlers-Danlos syndromes: Mechanisms, models, and challenges.

Chronic pain is one of the most common, yet poorly studied, complaints in people suffering from Ehlers-Danlos syndromes (EDS). This heterogeneous group of heritable connective tissue disorders is typically characterized by skin hyperextensibility, joint hypermobility, and generalized connective tissue fragility. Most EDS types are caused by genetic defects that affect connective tissue biosynthesis, thereby compromising collagen biosynthesis or fibrillogenesis and resulting in a disorganized extracellular matrix. Even though chronic pain is a major source of disability, functional impairment, and psychosocial suffering in EDS, currently used analgesics and other treatment strategies provide inadequate pain relief and thus represents an important unmet medical need. An important contributor to this is the lack of knowledge about the underlying mechanisms. In this narrative review, we summarize the current understanding of pain and the associated mechanisms in EDS based on clinical studies focusing on questionnaires and experimental pain testing as well as studies in animal models of EDS. In addition, we highlight the challenges, gaps, and opportunities in EDS-pain research.

Measurement properties of clinical assessment methods for classifying generalized joint hypermobility-A systematic review.

The purpose was to perform a systematic review of clinical assessment methods for classifying Generalized Joint Hypermobility (GJH), evaluate their clinimetric properties, and perform the best evidence synthesis of these methods. Four test assessment methods (Beighton Score [BS], Carter and Wilkinson, Hospital del Mar, Rotes-Querol) and two questionnaire assessment methods (Five-part questionnaire [5PQ], Beighton Score-self reported [BS-self]) were identified on children or adults. Using the Consensus-based Standards for selection of health Measurement Instrument (COSMIN) checklist for evaluating the methodological quality of the identified studies, all included studies were rated "fair" or "poor." Most studies were using BS, and for BS the reliability most of the studies showed limited positive to conflicting evidence, with some shortcomings on studies for the validity. The three other test assessment methods lack satisfactory information on both reliability and validity. For the questionnaire assessment methods, 5PQ was the most frequently used, and reliability showed conflicting evidence, while the validity had limited positive to conflicting evidence compared with test assessment methods. For BS-self, the validity showed unknown evidence compared with test assessment methods. In conclusion, following recommended uniformity of testing procedures, the recommendation for clinical use in adults is BS with cut-point of 5 of 9 including historical information, while in children it is BS with cut-point of at least 6 of 9. However, more studies are needed to conclude on the validity properties of these assessment methods, and before evidence-based recommendations can be made for clinical use on the "best" assessment method for classifying GJH. © 2017 Wiley Periodicals, Inc.

Hypermobility, the Ehlers-Danlos syndromes and chronic pain.

Chronic widespread pain is a common complaint among individuals affected by generalised joint hypermobility. In the absence of other conditions that cause chronic pain, these individuals are usually diagnosed with joint hypermobility syndrome (JHS). JHS is a multifactorial trait with a strong genetic basis, but no specific genetic markers. Clinical overlap of JHS is seen with heritable connective tissue disorders, particularly with the Ehlers-Danlos syndrome, hypermobile type (hEDS). The Ehlers-Danlos syndromes (EDS) comprise a heterogeneous group of rare monogenic conditions that are characterised by joint hypermobility, skin and vascular fragility and generalised connective tissue friability, and are caused by genetic defects in an array of extracellular matrix genes. The genetic basis of hEDS remains however unknown, in contrast to other well-described EDS subtypes. In view of the considerable clinical overlap with JHS, many consider it and hEDS to be a single clinical entity. Clinical experience and a limited number of clinical studies show that chronic pain also is common in EDS patients, especially in hEDS. The specific underlying causes and mechanisms of pain in JHS and EDS remain poorly understood. Factors likely contributing to the generation and chronicity of pain include nociceptive pain, directly based on structural changes in affected joints, muscle and connective tissue; neuropathic pain; impaired proprioception and muscle weakness; and central sensitisation. These mechanisms are not mutually exclusive, and likely more than one mechanism may be present. Furthermore, anxiety, depression, and other variables may influence the phenotype. Chronic pain in JHS and EDS patients often is inadequately controlled by traditional analgesics and physical therapy. In view of the high prevalence of these underrecognised conditions, future studies addressing the nature and mediators of chronic pain are needed in order to potentially identify novel targets for therapeutic intervention and optimise treatment.

Orthostatic intolerance and fatigue in the hypermobility type of Ehlers-Danlos Syndrome.

OBJECTIVE: To investigate whether orthostatic intolerance (OI) is a significant predictor for fatigue in Ehlers-Danlos Syndrome, hypermobility type (EDS-HT). METHODS: Eighty patients with EDS-HT and 52 controls participated in the first part of the study, which consisted of questionnaires. Fatigue was evaluated using the Checklist Individual Strength (CIS). As possible fatigue determinants OI [Autonomic Symptom Profile (ASP)], habitual physical activity (Baecke), affective distress [Hospital Anxiety and Depression Scale (HADS)], pain (SF36), medication use and generalized hypermobility (5-point score of Grahame and Hakim regarding generalized joint hypermobility) were studied. Next, a 20 min head-up tilt (70°) was performed in a subsample of 39 patients and 35 controls, while beat-to-beat heart rate and blood pressure were monitored (Holter, Finometer Pro). Before and after tilt, fatigue severity was assessed using a numeric rating scale. RESULTS: Patients scored significantly higher on the CIS [total score: EDS: 98.2 (18.63) vs controls: 45.8 (16.62), P < 0.001] and on the OI domain of the ASP [EDS: 22.78 (7.16) vs controls: 6.5 (7.78)]. OI was prevalent in EDS-HT (EDS: 74.4%, controls: 34.3%, P = 0.001), and frequently expressed as postural orthostatic tachycardia (41.0% of the EDS group). Patients responded to tilt with a higher heart rate and lower total peripheral resistance (p < 0.001; p = 0.032). This altered response correlated with fatigue in daily life (CIS). In the EDS-HT group, tilt provoked significantly more fatigue [numeric rating scale increase: EDS: +3.1 (1.90), controls: +0.5 (1.24), P < 0.001]. Furthermore, the factors OI, pain, affective distress, decreased physical activity and sedative use explained 47.7% of the variance in fatigue severity. CONCLUSION: OI is an important determinant of fatigue in EDS-HT.

Disability in Adolescents and Adults Diagnosed With Hypermobility-Related Disorders: A Meta-Analysis.

OBJECTIVE: To (1) establish the association of the most common reported symptoms on disability; and (2) study the effectiveness of treatment on disability in patients with Ehlers-Danlos syndrome-hypermobility type (EDS-HT)/hypermobility syndrome (HMS). DATA SOURCES: An electronic search (Medical Subject Headings and free-text terms) was conducted in bibliographic databases CENTRAL/MEDLINE. STUDY SELECTION: Comparative, cross-sectional, longitudinal cohort studies and (randomized) controlled trials including patients with HMS/EDS-HT aged ≥17 years were considered for inclusion. A class of symptoms was included when 5 publications were available. In regards to treatment (physical, cognitive interventions), only (randomized) controlled trials were considered. Surgical and medicinal interventions were excluded. DATA EXTRACTION: Bias was assessed according to the methodological scoring tools of the Cochrane collaboration. Z-score transformations were applied to classify the extent of disability in comparison with healthy controls and to ensure comparability between studies. DATA SYNTHESIS: Initially, the electronic search yielded 714 publications, and 21 articles remained for analysis after selection. The following symptoms were included for meta-analysis: pain (n=12), fatigue (n=6), and psychological distress (n=7). Pain (r=.64, P=.021), fatigue (r=.91, P=.011), and psychological distress (r=.86, P=.018) had a significant impact on disability. Regarding treatment, a significant pain reduction was achieved by a variety of physical and cognitive approaches. Treatment effectiveness on disability was not established. CONCLUSIONS: Disability can affect patients with HMS/EDS-HT significantly and is highly correlated with both physical and psychological factors. Although evidence is available that physical and psychological treatment modalities can induce significant pain reduction, the evidence regarding disability reduction is lacking.

Knowledge, assessment, and management of adults with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type among Flemish physiotherapists.

Physiotherapy plays a fundamental role in managing adults with the joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT). However, it is a challenge for both the patient and the physiotherapist as the condition is poorly understood and treatment for JHS/EDS-HT is currently undefined. Insight into current practice is, therefore, necessary in order to establish baseline knowledge in this area and in the long term to improve the standard of patient care. Therefore, the purpose of this study was to evaluate current physiotherapists' knowledge of JHS/EDS-HT and to gain insight into current physiotherapy practice with emphasis on assessment, management, and treatment efficacy. Three hundred twenty-five Flemish physiotherapists participated in the study by filling out electronically a modified version of the "Hypermobility and Hypermobility Syndrome Questionnaire" (HHQ), which covered theoretical constructs such as general knowledge, assessment, management, and learning in relation to generalized joint hypermobility and JHS/EDS-HT. The results show that physiotherapists report a low level of confidence with regard to assessment and management of JHS/EDS-HT. Knowledge of hypermobility and JHS/EDS-HT is weak, especially regarding the features associated with JHS/EDS-HT. Many treatment approaches are used by physiotherapists with the majority showing preference for education, reassurance, muscle strengthening, proprioceptive and core stability training. Almost all approaches were perceived as being clinically effective by the physiotherapists, highlighting a lack of consensus. In conclusion, this study in Flemish physiotherapists confirms that JHS/EDS-HT is under-recognized, not well known and deemed difficult to treat. Further education is required and sought by the physiotherapists surveyed, and future research is needed.

The influence of sprint interval training on body composition, physical and metabolic fitness in adolescents and young adults with intellectual disability: a randomized controlled trial.

OBJECTIVE: In this study we evaluated the effect of sprint interval training on metabolic and physical fitness in adolescents and young adults with intellectual disabilities when compared with continuous aerobic training and no training (control). METHODS: Fifty-four persons with intellectual disabilities (age: 17 (3.0), body mass index: 27.7 (3.7), intelligence quotient: 59 (8.6)) were matched based on age, gender and intelligence quotient between sprint interval training (n = 17), continuous aerobic training (n = 15) and control (n = 14). Sprint interval training was composed of three blocks of 10 minutes at ventilatory threshold (blocks 1 and 3: 10 sprint bouts of 15 seconds, followed by 45 seconds relative rest; block 2: continuous training) twice a week for 15 weeks. Continuous aerobic training was composed of three blocks of 10 minutes continuous training. After eight weeks, intensity was increased to 110% of ventilatory threshold. The control group did not participate in supervised exercise training. Before and after the training period, body composition, physical and metabolic fitness were evaluated. RESULTS: Sprint interval training showed a significant positive evolution for waist circumference, fat%, systolic blood pressure, lipid profile, fasting insulin, homeostasis model assessment of insulin resistance, peak VO2, peak Watt, ventilatory threshold, 6-minute walk distance and muscle fatigue resistance when compared with no training (P < 0.01). The sprint interval training group demonstrated significant improvements for fat%, systolic blood pressure, low-density lipoprotein, fasting insulin, peak VO2 and peak power and ventilatory threshold (P < 0.01) when compared with continuous aerobic training. CONCLUSION: In this study we could observe that sprint interval training has stronger beneficial effects on body composition, physical fitness and metabolic fitness compared with control. Compared with continuous aerobic training, sprint interval training seems to result in better outcome.

Bone parameters in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder: A comparative cross-sectional study.

OBJECTIVE: To compare bone parameters between individuals with hypermobile Ehlers-Danlos syndrome (hEDS) and generalized joint hypermobility spectrum disorder (G-HSD), both diagnosed according to the most recent diagnostic criteria, and with controls. METHODS: Twenty female adults with hEDS (mean age 43.8 years), 20 with G-HSD (mean age 41.8 years), and 37 healthy controls (mean age 40.8 years) participated. Body composition and bone parameters at whole body and lumbar spine were assessed by dual-energy X-ray absorptiometry. Peripheral quantitative computed tomography at the lower leg evaluated body composition (66 % site), and trabecular (4 % site) and cortical (66 % site) bone parameters at the tibia. RESULTS: No significantly different body composition and bone parameters were observed between hEDS and G-HSD. Compared to controls, individuals with hEDS and G-HSD had lower muscle mass (p = 0.004 and p < 0.001, respectively) and cross-sectional area (p = 0.025 and p < 0.001, respectively), cortical bone mineral content (BMC; p = 0.024 and p = 0.027, respectively) and area (p = 0.019 and p = 0.010, respectively). Additionally, individuals with hEDS had lower muscle density (p = 0.009), trabecular BMC (p = 0.027) and bone mineral density (p = 0.022), and individuals with G-HSD lower stress-strain index (p = 0.019), and periosteal and endosteal circumference (p = 0.002 and 0.025, respectively), compared to controls. CONCLUSION: Results indicated lower cortical bone mineral content and smaller cortices in hEDS and G-HSD compared to controls. Individuals with hEDS and G-HSD had no different bone parameters, suggesting that these impairments might not be reflected by the different diagnostic classification. Therefore, we recommend regular physical activity, and training to reduce the risk of falling in both hEDS or G-HSD.

Sensory profiling in classical Ehlers-Danlos syndrome: a case-control study revealing pain characteristics, somatosensory changes, and impaired pain modulation.

Pain is one of the most important, yet poorly understood complaints in heritable connective tissue disorders (HCTD) caused by monogenic defects in extracellular matrix molecules. This is particularly the case for Ehlers-Danlos syndromes (EDS), paradigm collagen-related disorders. This study aimed to identify the pain signature and somatosensory characteristics in the rare classical type of EDS (cEDS) caused by defects in type V or rarely type I collagen. We used static and dynamic quantitative sensory testing and validated questionnaires in 19 individuals with cEDS and 19 matched controls. Individuals with cEDS reported clinically relevant pain/discomfort (VAS ≥5/10 in 32% for average pain intensity the past month) and worse health -related quality of life. Altered sensory profile was found in the cEDS group with higher (p=0.04) detection thresholds for vibration stimuli at the lower limb indicating hypoesthesia, reduced thermal sensitivity with more (p<0.001) paradoxical thermal sensations, and hyperalgesia with lower pain thresholds to mechanical (p<0.001) stimuli at both the upper and lower limbs and to cold (p=0.005) stimulation at the lower limb. Using a parallel conditioned pain paradigm, the cEDS group showed significantly smaller antinociceptive responses (p-value between 0.005 and 0.046) suggestive of impaired endogenous central pain modulation. In conclusion, Individuals with cEDS report chronic pain and worse health-related quality of life, and present altered somatosensory perception. This study is the first to systematically investigate pain and somatosensory characteristics in a genetically defined HCTD and provides interesting insights on the possible role of the ECM in the development and persistence of pain.

Sensory Profiling in Classical Ehlers-Danlos Syndrome: A Case-Control Study Revealing Pain Characteristics, Somatosensory Changes, and Impaired Pain Modulation.

Pain is one of the most important yet poorly understood complaints in heritable connective tissue disorders (HCTDs) caused by monogenic defects in extracellular matrix molecules. This is particularly the case for the Ehlers-Danlos syndrome (EDS), paradigm collagen-related disorders. This study aimed to identify the pain signature and somatosensory characteristics in the rare classical type of EDS (cEDS) caused by defects in type V or rarely type I collagen. We used static and dynamic quantitative sensory testing and validated questionnaires in 19 individuals with cEDS and 19 matched controls. Individuals with cEDS reported clinically relevant pain/discomfort (Visual Analogue Scale ≥5/10 in 32% for average pain intensity the past month) and worse health-related quality of life. An altered somatosensory profile was found in the cEDS group with higher (P = .04) detection thresholds for vibration stimuli at the lower limb, indicating hypoesthesia, reduced thermal sensitivity with more (P < .001) paradoxical thermal sensations (PTSs), and hyperalgesia with lower pain thresholds to mechanical (P < .001) stimuli at both the upper and lower limbs and cold (P = .005) stimulation at the lower limb. Using a parallel conditioned pain modulation paradigm, the cEDS group showed significantly smaller antinociceptive responses (P-value .005-.046) suggestive of impaired endogenous pain modulation. In conclusion, individuals with cEDS report chronic pain and worse health-related quality of life and present altered somatosensory perception. This study is the first to systematically investigate pain and somatosensory characteristics in a genetically defined HCTD and provides interesting insights into the possible role of the ECM in the development and persistence of pain. PERSPECTIVE: Chronic pain compromises the quality of life in individuals with cEDS. Moreover, an altered somatosensory perception was found in the cEDS group with hypoesthesia for vibration stimuli, more PTSs, hyperalgesia for pressure stimuli, and impaired pain modulation.

Physical activity and physical fitness in children with heritable connective tissue disorders.

Objectives: Health problems in patients with heritable connective tissue disorders (HCTD) are diverse and complex and might lead to lower physical activity (PA) and physical fitness (PF). This study aimed to investigate the PA and PF of children with heritable connective tissue disorders (HCTD). Methods: PA was assessed using an accelerometer-based activity monitor (ActivPAL) and the mobility subscale of the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT). PF was measured in terms of cardiovascular endurance using the Fitkids Treadmill Test (FTT); maximal hand grip strength, using hand grip dynamometry (HGD) as an indicator of muscle strength; and motor proficiency, using the Bruininks-Oseretsky Test of Motor Proficiency-2 (BOTMP-2). Results: A total of 56 children, with a median age of 11.6 (interquartile range [IQR], 8.8-15.8) years, diagnosed with Marfan syndrome (MFS), n = 37, Loeys-Dietz syndrome (LDS), n = 6, and genetically confirmed Ehlers-Danlos (EDS) syndromes, n = 13 (including classical EDS n = 10, vascular EDS n = 1, dermatosparaxis EDS n = 1, arthrochalasia EDS n = 1), participated. Regarding PA, children with HCTD were active for 4.5 (IQR 3.5-5.2) hours/day, spent 9.2 (IQR 7.6-10.4) hours/day sedentary, slept 11.2 (IQR 9.5-11.5) hours/day, and performed 8,351.7 (IQR 6,456.9-1,0484.6) steps/day. They scored below average (mean (standard deviation [SD]) z-score -1.4 (1.6)) on the PEDI-CAT mobility subscale. Regarding PF, children with HCTD scored well below average on the FFT (mean (SD) z-score -3.3 (3.2)) and below average on the HGD (mean (SD) z-score -1.1 (1.2)) compared to normative data. Contradictory, the BOTMP-2 score was classified as average (mean (SD) z-score.02 (.98)). Moderate positive correlations were found between PA and PF (r(39) = .378, p < .001). Moderately sized negative correlations were found between pain intensity and fatigue and time spent actively (r(35) = .408, p < .001 and r(24) = .395 p < .001, respectively). Conclusion: This study is the first to demonstrate reduced PA and PF in children with HCTD. PF was moderately positively correlated with PA and negatively correlated with pain intensity and fatigue. Reduced cardiovascular endurance, muscle strength, and deconditioning, combined with disorder-specific cardiovascular and musculoskeletal features, are hypothesized to be causal. Identifying the limitations in PA and PF provides a starting point for tailor-made interventions.

Impairment and impact of pain in female patients with Ehlers-Danlos syndrome: a comparative study with fibromyalgia and rheumatoid arthritis.

OBJECTIVE: The purpose of this study was to investigate functional impairment and the impact of pain in patients with Ehlers-Danlos syndrome, hypermobility type (EDS-HT), and to compare the burden of disease with that in women with fibromyalgia (FM) and rheumatoid arthritis (RA). METHODS: A total of 206 female patients were compared (72 with EDS-HT, 69 with FM, and 65 with RA). Functional impairment was assessed with the Sickness Impact Profile (SIP), and the psychosocial impact of chronic pain was quantified with the Multidimensional Pain Inventory (MPI). Data on symptoms were collected. RESULTS: SIP results showed clinically relevant health-related dysfunction in all groups. Significantly poorer physical, psychosocial, and overall function was found in the EDS-HT group compared with the RA group. In comparison with the FM group, the EDS-HT group reported similar physical and overall function, but better psychosocial function. T scores from the MPI revealed significantly higher levels of pain severity and life interference due to pain, and a lower level of perceived life control, in the EDS-HT group compared to the RA group. In contrast, the EDS-HT group showed significantly lower levels of pain severity, life interference, and affective distress in comparison with the FM group. Social support for help in coping with pain was similar between the 3 groups. CONCLUSION: EDS-HT is associated with a consistent burden of disease, similar to that of FM and worse than that of RA, as well as a broad impact of chronic pain on daily life, which needs to be addressed in the health care system.

Exploring pain mechanisms in hypermobile Ehlers-Danlos syndrome: A case-control study.

BACKGROUND: The hypermobile type of Ehlers-Danlos syndrome (hEDS) is a heritable connective tissue disorder, associated with joint hypermobility and prominent chronic pain. Because experimental pain testing in hEDS is scarce, the underlying mechanisms are still poorly understood. OBJECTIVE: The present study assesses endogenous pain facilitation and pain inhibition in hEDS, using a protocol for temporal summation of pain (TSP), conditioned pain modulation (CPM) and exercise-induced hypoalgesia (EIH). METHODS: Twenty women with hEDS and 20 age-matched healthy controls participated. After evaluating thermal and mechanical pain thresholds (PPT), TSP was assessed using 10 repetitive painful pressure stimuli. CPM was provoked using pressure as the test stimulus and hand immersion in hot water (46°) as the conditioning stimulus. EIH was assessed after a submaximal cycling protocol. RESULTS: The hEDS group demonstrated reduced PPTs and showed significantly more TSP after repeated painful stimuli than the control group. In comparison to the healthy control group, the hEDS group demonstrated significantly less EIH at the quadriceps test location. At the trapezius, EIH did not significantly differ between groups. No significant differences were found between the hEDS group and control group in the CPM response. CONCLUSION: The results demonstrate increased TSP in hEDS, suggesting increased central pain facilitation. EIH should be studied more extensively but may be disturbed when evaluated in the muscles that are activated during exercise. The CPM results are inconclusive and require more research. SIGNIFICANCE: Studies regarding the mechanisms that underlie pain in hEDS are scarce, although it is the most prevalent and disabling symptom in this patient population. This study demonstrates increased temporal summation in hEDS and suggests that exercise-induced hypoalgesia may be reduced. Because exercise is a cornerstone in the multidisciplinary treatment of heritable connective tissue disorders, gaining knowledge in this field is important. Pressure stimuli were used to facilitate the international usability of the protocols, allowing for future data acquisition in large cohorts.

Altered Multisegment Ankle and Foot Kinematics During Gait in Patients With Hypermobile Ehlers-Danlos Syndrome/Hypermobility Spectrum Disorder: A Case-Control Study.

OBJECTIVE: Ankle-foot problems have a considerable impact on daily functioning in patients with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder (hEDS/HSD). Therefore, the objective of this study was to identify alterations in multisegment ankle and foot kinematics during gait and to assess foot function and pain in these patients. METHODS: Twenty-three women with hEDS/HSD and 23 healthy controls participated in this 3-dimensional gait analysis. Multisegment ankle and foot kinematics were collected using the Ghent Foot Model and analyzed with Statistical Parametric Mapping. Foot function and pain were assessed using visual analog scale scores, the Margolis Pain Diagram, and the Foot Function Index. RESULTS: Levels of pain and foot dysfunction were significantly higher in subjects with hEDS/HSD (P < 0.001). Kinematic curve analyses provide evidence for a hypermobile first ray, represented by a significantly increased eversion position of the medial forefoot during stance phase (P < 0.001) in subjects with hEDS/HSD compared to controls. In addition, significantly more dorsiflexion was found in the medial and lateral forefoot and the rearfoot (P < 0.001). At the midfoot, an increased plantar flexion (P < 0.001) and at the level of the hallux a decreased dorsiflexion (P = 0.037) and increased inversion (P < 0.001) and abduction (P = 0.016) were found in subjects with hEDS/HSD. CONCLUSION: This study is the first to apply a multisegment foot model during gait in hEDS/HSD, which confirms the characteristic hypermobility throughout the foot, especially the hypermobile first ray.

Medication, surgery, and physiotherapy among patients with the hypermobility type of Ehlers-Danlos syndrome.

OBJECTIVES: To describe medication use, surgery, and physiotherapy, and to examine the effect of these treatment modalities on functional impairment and amount of complaints among patients with the hypermobility type of Ehlers-Danlos syndrome (EDS-HT). DESIGN: Cross-sectional study. SETTING: Physical and rehabilitation medicine department and center for medical genetics. PARTICIPANTS: Patients with EDS-HT (N=79; 8 men, 71 women) were recruited for this study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients filled out questionnaires regarding type of complaints, medication use, surgery, physiotherapy, and outcome of treatment. Functional impairment in daily life was measured by the Sickness Impact Profile. Pain severity was assessed with visual analog scales. RESULTS: Patients reported a large number of complaints, a considerable presence of severe pain, and a clinically significant impact of disease on daily functioning. Most patients (92.4%) used medications, among which analgesics were the most prevalent. Fifty-six patients (70.9%) underwent surgery, including mainly interventions of the extremities and abdomen. Forty-one patients (51.9%) are currently enrolled in a physical therapy program, mainly comprising neuromuscular exercises, massage, and electrotherapy. Patients with a high consumption of analgesics, who visited the physiotherapist, or who underwent surgery had a higher dysfunction in daily life. Only 33.9% of the patients who underwent surgery and 63.4% of patients in physical therapy reported a positive outcome. CONCLUSIONS: Patients with EDS-HT have numerous complaints and an impaired functional status that strongly determine their high rate of treatment consumption. The outcome of surgical and physiotherapy treatment is disappointing in a large percentage, which illustrates a strong need for evidence-based therapy.