Generalized joint hypermobility (GJH) is highly prevalent among patients diagnosed with chronic pain. When GJH is accompanied by pain in ≥4 joints over a period ≥3 months in the absence of other conditions that cause chronic pain, the hypermobility syndrome (HMS) may be diagnosed. In addition, GJH is also a clinical sign that is frequently present in hereditary diseases of the connective tissue, such as the Marfan syndrome, osteogenesis imperfecta, and the Ehlers-Danlos syndrome. However, within the Ehlers-Danlos spectrum, a similar subcategory of patients having similar clinical features as HMS but lacking a specific genetic profile was identified: Ehlers-Danlos syndrome hypermobility type (EDS-HT). Researchers and clinicians have struggled for decades with the highly diverse clinical presentation within the HMS and EDS-HT phenotypes (Challenge 1) and the lack of understanding of the pathological mechanisms that underlie the development of pain and its persistence (Challenge 2). In addition, within the HMS/EDS-HT phenotype, there is a high prevalence of psychosocial factors, which again presents a difficult issue that needs to be addressed (Challenge 3). Despite recent scientific advances, many obstacles for clinical care and research still remain. To gain further insight into the phenotype of HMS/EDS-HT and its mechanisms, clearer descriptions of these populations should be made available. Future research and clinical care should revise and create consensus on the diagnostic criteria for HMS/EDS-HT (Solution 1), account for clinical heterogeneity by the classification of subtypes within the HMS/EDS-HT spectrum (Solution 2), and create a clinical core set (Solution 3).
We report on an autosomal-recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine. Clinically, the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Linkage analysis in a large Tyrolean kindred identified a homozygous frameshift mutation in FKBP14 in two affected individuals. Based on the cardinal clinical characteristics of the disorder, four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in FKBP14. FKBP14 belongs to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases). ER-resident FKBPs have been suggested to act as folding catalysts by accelerating cis-trans isomerization of peptidyl-prolyl bonds and to act occasionally also as chaperones. We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro. These findings suggest that a disturbance of protein folding in the ER affecting one or more components of the extracellular matrix might cause the generalized connective tissue involvement in this disorder. FKBP14 mutation analysis should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment.
EDS-HT is a connective tissue disorder characterized by large inter-individual differences in the clinical presentation, complicating diagnosis and treatment. We aim to describe the clinical heterogeneity and to investigate whether differences in the symptom profile are also reflected as disparity in functional impairment and pain experience. In this study, 78 patients were asked to describe their symptoms due to EDS-HT. Next, a hierarchical cluster analysis was performed using the Jaccard measure of similarity to assess whether subgroups could be distinguished based on the symptoms reported. This analysis yielded 3 clusters of participants with distinct complaint profiles. The key differences were found in the domain of non-musculoskeletal complaints, which was significantly larger in cluster 2. Furthermore, cluster 2 was characterized by a worse physical and psychosocial health, a higher pain severity and a larger pain interference in daily life. The results emphasize that non-musculoskeletal symptoms are an important complication of EDS-HT, as the number of these complaints was found to be a significant predictor for both functional health status (SIP) and pain experience (MPI). In conclusion, this study confirms that EDS-HT is a heterogeneous entity and encourages the clinician to be more aware of the large variety of EDS-HT symptoms, in order to improve disease recognition and to establish more tailored treatment strategies.
We report a 34-year-old Japanese female with the vascular type of Ehlers-Danlos syndrome. She had thin translucent skin, extensive bruising, toe joint hypermobility, left lower extremity varicose veins, and chronic wrist, knee and ankle joint pain. She also had dizziness caused by autonomic dysfunction. Magnetic resonance angiography showed tortuous vertebral and basilar arteries, mild left carotid canal bulging, and right anterior tibial artery hypoplasia. Electron microscopic examinations of a skin biopsy revealed extremely dilated rough endoplasmic reticulum in dermal fibroblasts and wide variability of individual collagen fibril diameters. A molecular analysis using a conventional total RNA method and a high-resolution melting curve analysis using genomic DNA revealed a novel missense mutation within exon 48 of the COL3A1 gene, c.3428G>A, leading to p.Gly1143Glu.
Low tendon stiffness and abnormal ultrastructure distinguish classic Ehlers-Danlos syndrome from benign joint hypermobility syndrome in patients
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Published almost 6 years ago
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.-Nielsen, R. H., Couppé, C., Jensen, J. K., Olsen, M. R., Heinemeier, K. M., Malfait, F., Symoens, S., De Paepe, A., Schjerling, P., Magnusson, S. P., Remvig, L., Kjaer, M. Low tendon stiffness and abnormal ultrastructure distinguish classic Ehlers-Danlos syndrome from benign joint hypermobility syndrome in patients.
Joint Hypermobility Syndrome, also known as Ehlers-Danlos Syndrome Hypermobility Type (JHS/EDS-HT), is a heritable disorder of connective tissue, common but poorly known by the medical community. Although generalized joint hypermobility and fragility of tissues have been described as core features, recent research highlights the multisystemic nature of JHS/EDS-HT, which presents with a wide range of articular and extra-articular symptoms. Among these, gastrointestinal problems, temporomandibular disorders, and smell and taste abnormalities are common among those affected, having significant implications for eating. The present work reviews the literature linking JHS/EDS-HT and eating problems. Two illustrative case reports, in which JHS/EDS-HT manifestations contribute to developing and maintaining disturbed eating behaviors and significant weight loss, are presented.
Neurodevelopmental attributes of joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type: Update and perspectives
- American journal of medical genetics. Part C, Seminars in medical genetics
- Published over 5 years ago
In the last decade, increasing attention has been devoted to the extra-articular and extra-cutaneous manifestations of joint hypermobility syndrome, also termed Ehlers-Danlos syndrome, hypermobility type (i.e., JHS/EDS-HT). Despite the fact that the current diagnostic criteria for both disorders remain focused on joint hypermobility, musculoskeletal pain and skin changes, medical practice and research have started investigating a wide spectrum of visceral, neurological and developmental complications, which represent major burdens for affected individuals. In particular, children with generalized joint hypermobility often present with various neurodevelopmental issues and can be referred for neurological consultation. It is common that investigations in these patients yield negative or inconsistent results, eventually leading to the exclusion of any structural neurological or muscle disorder. In the context of specialized clinics for connective tissue disorders, a clear relationship between generalized joint hypermobility and a characteristic neurodevelopmental profile affecting coordination is emerging. The clinical features of these patients tend to overlap with those of developmental coordination disorder and can be associated with learning and other disabilities. Physical and psychological consequences of these additional difficulties add to the chief manifestations of the pre-existing connective tissue disorder, affecting the well-being and development of children and their families. In this review, particular attention is devoted to the nature of the link between joint hypermobility, coordination difficulties and neurodevelopmental issues in children. Presumed pathogenesis and management issues are explored in order to attract more attention on this association and nurture future clinical research. © 2015 Wiley Periodicals, Inc.
In this case study, biomechanical alterations induced by neuromuscular taping (NMT) were quantified, during walking, in a patient with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT).
The role of physical trauma in the onset of symptoms in Ehlers-Danlos syndrome (EDS) has never been characterized. We sought to search and describe brain lesions EDS patients also having personal history of physical trauma. We systematically performed brain magnetic resonance imaging in a first cohort of patients with a hypermobility type of EDS which described the onset of their disease or its worsening after a physical trauma. Unexpected yet consistent findings that were thought to be related to the reported traumas led to perform brain imaging in all subsequent patients with similar symptoms regardless of a history of trauma and to search for a prior trauma by active questioning.
To assess the risk of psychiatric disorders in Ehlers-Danlos syndrome (EDS) and hypermobility syndrome.