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Pathogenic variants in COL1A1 and COL1A2 are involved in osteogenesis imperfecta (OI) and, rarely, Ehlers-Danlos syndrome (EDS) subtypes and OI-EDS overlap syndromes (OIEDS1 and OIEDS2, respectively). Here we describe a cohort of 34 individuals with likely pathogenic and pathogenic variants in COL1A1 and COL1A2, 15 of whom have potential OIEDS1 (n = 5) or OIEDS2 (n = 10). A predominant OI phenotype and COL1A1 frameshift variants are present in 4/5 cases with potential OIEDS1. On the other hand, 9/10 potential OIEDS2 cases have a predominant EDS phenotype, including four with an initial diagnosis of hypermobile EDS (hEDS). An additional case with a predominant EDS phenotype had a COL1A1 arginine-to-cysteine variant that was originally misclassified as a variant of uncertain significance despite this type of variant being associated with classical EDS with vascular fragility. Vascular/arterial fragility was observed in 4/15 individuals (including one individual with an original diagnosis of hEDS), which underscores the unique clinical surveillance and management needs in these patients. In comparison to previously described OIEDS1/2, we observed differentiating features that should be considered to refine currently proposed criteria for genetic testing in OIEDS, which will be beneficial for diagnosis and management. Additionally, these results highlight the importance of gene-specific knowledge for informed variant classification and point to a potential genetic resolution (COL1A2) for some cases of clinically diagnosed hEDS., (© 2023 Wiley Periodicals LLC.)

The Ehlers-Danlos syndromes (EDS) are hereditary disorders that affect the connective tissue and collagen structures in the body. Several types of EDS have been identified. Oral and mandibular structures, which include oral soft tissue, dentition, facial and head pain, and the functioning of the temporomandibular joint (TMJ), are variably affected in the various types of EDS. These various manifestations of EDS have been noted for many years, but newer diagnostic techniques and studies are shedding additional light on the challenges faced by EDS patients in the area of oral and mandibular disorders. Further, the impact of temporomandibular disorder (TMD) on musculoskeletal dysfunction and vice versa, make this an important feature to recognize. Oral and mandibular hypermobility of the TMJ with associated consequences of EDS are noted. These features, diagnostic parameters and treatment procedures are presented. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Well known for their role in allergic disorders, mast cells (MCs) play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury, with an array of chemical mediators. After being recruited to connective tissues, resident MCs progenitors undergo further differentiation, under the influence of signals from surrounding microenvironment. It is the differential tissue homing and local maturation factors which result in a diverse population of resident MC phenotypes. An abundance of MC reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts). Situated near nerve fibers, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, MCs can modulate the function of local and distant structures (e.g., other immune cell populations, fibroblasts, angiogenesis), and MC dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders (CTDs). This report reviews basic biology of mast cells and mast cell activation as well as recent research efforts, which implicate a role of MC dysregulation beyond atopic disorders and in a cluster of Ehlers-Danlos Syndromes, non-IGE mediated hypersensitivity disorders, and dysautonomia. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The hypermobile type of Ehlers-Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue. It has been described largely in those with musculoskeletal complaints including joint hypermobility, joint subluxations/dislocations, as well as skin and soft tissue manifestations. Many patients report activity-related pain and some go on to have daily pain. Two undifferentiated syndromes have been used to describe these manifestations-joint hypermobility syndrome and hEDS. Both are clinical diagnoses in the absence of other causation. Current medical literature further complicates differentiation and describes multiple associated symptoms and disorders. The current EDS nosology combines these two entities into the hypermobile type of EDS. Herein, we review and summarize the literature as a better clinical description of this type of connective tissue disorder. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

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

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin extensibility, and tissue fragility. This communication briefly reports upon the neurological manifestations that arise including the weakness of the ligaments of the craniocervical junction and spine, early disc degeneration, and the weakness of the epineurium and perineurium surrounding peripheral nerves. Entrapment, deformation, and biophysical deformative stresses exerted upon the nervous system may alter gene expression, neuronal function and phenotypic expression. This report also discusses increased prevalence of migraine, idiopathic intracranial hypertension, Tarlov cysts, tethered cord syndrome, and dystonia, where associations with EDS have been anecdotally reported, but where epidemiological evidence is not yet available. Chiari Malformation Type I (CMI) has been reported to be a comorbid condition to EDS, and may be complicated by craniocervical instability or basilar invagination. Motor delay, headache, and quadriparesis have been attributed to ligamentous laxity and instability at the atlanto-occipital and atlantoaxial joints, which may complicate all forms of EDS. Discopathy and early degenerative spondylotic disease manifest by spinal segmental instability and kyphosis, rendering EDS patients prone to mechanical pain, and myelopathy. Musculoskeletal pain starts early, is chronic and debilitating, and the neuromuscular disease of EDS manifests symptomatically with weakness, myalgia, easy fatigability, limited walking, reduction of vibration sense, and mild impairment of mobility and daily activities. Consensus criteria and clinical practice guidelines, based upon stronger epidemiological and pathophysiological evidence, are needed to refine diagnosis and treatment of the various neurological and spinal manifestations of EDS. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Tenascin-X is an extracellular matrix protein initially identified because the gene encoding it overlaps with the human CYP21B gene. Because studies of gene and protein function of other tenascins had been poorly predictive of essential functions in vivo, we used a genetic approach that critically relied on an understanding of the genomic locus to uncover an association between inactivating tenascin-X mutations and novel recessive and dominant forms of Ehlers-Danlos syndrome (EDS). Tenascin-X provides the first example of a gene outside of the fibrillar collagens and their processing enzymes that causes EDS. Tenascin-X null mice recapitulate the skin findings of the human disease, confirming a causative role for this gene in EDS. Further evaluation of these mice showed that tenascin-X is an important regulator of collagen deposition in vivo, suggesting a novel mechanism of disease in this form of EDS. Further studies suggest that tenascin-X may do this through both direct and indirect interactions with the collagen fibril. Recent studies show that TNX effects on matrix extend beyond the collagen to the elastogenic pathway and matrix remodeling enzymes. Tenascin-X serves as a compelling example of how human "experiments of nature" can guide us to an understanding of genes whose function may not be evident from their sequence or in vitro studies of their encoded proteins., (2005 Wiley-Liss, Inc.)

Classic Ehlers-Danlos syndrome is a heritable disorder of connective tissue that is characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. Mutations in the COL5A1 and the COL5A2 gene, encoding the alpha1 and the alpha2-chain of type V collagen respectively, are identified in approximately 50% of patients with a clinical diagnosis of classic EDS. In approximately one third of patients, the disease is caused by a mutation leading to a non-functional COL5A1 allele, and resulting in haplo-insufficiency of type V collagen. In a smaller proportion of patients, a structural mutation in COL5A1 or COL5A2, resulting in the production of a functionally defective type V collagen protein, is responsible for the phenotype. Inter- and intrafamilial phenotypic variability is observed, but no genotype-phenotype correlations can be made so far. The relatively low mutation detection rate in the COL5A1/A2 genes suggests genetic heterogeneity. Indeed rarely mutations in type I collagen have been identified in patients with classic EDS. Mutations in the gene for tenascin-X have been implicated in an autosomal recessive condition phenotypically overlapping with classic EDS. Several other candidate genes, such as decorin, have emerged from the study of transgenic mouse models with clinical and ultrastructural features reminiscent of classic EDS. However, to date, no human examples have been reported for these mouse models., (2005 Wiley-Liss, Inc.)