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Vascular Ehlers–Danlos syndrome (vEDS) is a rare autosomal dominant connective tissue disease resulting from pathogenic variants in the collagen type III alpha 1 chain (COL3A1) gene, encoding type III procollagen. Patients with vEDS present with severe tissue fragility that can result in arterial aneurysm, dissection, or rupture, especially of medium-caliber vessels. Although early reports have indicated a very high mortality rate in affected patients, with an estimated median survival of around 50 years, recent times have seen a remarkable improvement in outcomes in this population. This shift could be related to greater awareness of the disease among patients and physicians, with improved management both in terms of follow-up and treatment of complications. Increasing use of drugs acting on the cardiovascular system may also have contributed to this improvement. In particular, celiprolol, a β1 cardio-selective blocker with a β2-agonist vasodilator effect, has been shown to reduce rates of vascular events in patients with vEDS. However, the evidence on the true benefits and possible mechanisms responsible for the protective effect of celiprolol in this specific setting remains limited. Drugs targeting the extracellular matrix organization and autophagy–lysosome pathways are currently under investigation and could play a role in the future. This narrative review aims to summarize current evidence and future perspectives on vEDS medical treatment, with a specific focus on vascular prevention. [ABSTRACT FROM AUTHOR]

Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders. [ABSTRACT FROM AUTHOR]

The αvβ3 integrin, an endothelial cells' receptor-binding fibronectin (FN) in the extracellular matrix (ECM) of blood vessels, regulates ECM remodeling during migration, invasion, angiogenesis, wound healing and inflammation, and is also involved in the epithelial mesenchymal transition. In vitro-grown human control fibroblasts organize a fibrillar network of FN, which is preferentially bound on the entire cell surface to its canonical α5β1 integrin receptor, whereas the αvβ3 integrin is present only in rare patches in focal contacts. We report on the preferential recruitment of the αvβ3 integrin, due to the lack of FN-ECM and its canonical integrin receptor, in dermal fibroblasts from Ehlers-Danlos syndromes (EDS) and arterial tortuosity syndrome (ATS), which are rare multisystem connective tissue disorders. We review our previous findings that unraveled different biological mechanisms elicited by the αvβ3 integrin in fibroblasts derived from patients affected with classical (cEDS), vascular (vEDS), hypermobile EDS (hEDS), hypermobility spectrum disorders (HSD), and ATS. In cEDS and vEDS, respectively, due to defective type V and type III collagens, αvβ3 rescues patients' fibroblasts from anoikis through a paxillin-p60Src-mediated cross-talk with the EGF receptor. In hEDS and HSD, without a defined molecular basis, the αvβ3 integrin transduces to the ILK-Snail1-axis inducing a fibroblast-to-myofibroblast-transition. In ATS cells, the deficiency of the dehydroascorbic acid transporter GLUT10 leads to redox imbalance, ECM disarray together with the activation of a non-canonical αvβ3 integrin-TGFBRII signaling, involving p125FAK/p60Src/p38MAPK. The characterization of these different biological functions triggered by αvβ3 provides insights into the multifaced nature of this integrin, at least in cultured dermal fibroblasts, offering future perspectives for research in this field. [ABSTRACT FROM AUTHOR]

GLUT10 belongs to a family of transporters that catalyze the uptake of sugars/polyols by facilitated diffusion. Loss-of-function mutations in the SLC2A10 gene encoding GLUT10 are responsible for arterial tortuosity syndrome (ATS). Since subcellular distribution of the transporter is dubious, we aimed to clarify the localization of GLUT10. In silico GLUT10 localization prediction suggested its presence in the endoplasmic reticulum (ER). Immunoblotting showed the presence of GLUT10 protein in the microsomal, but not in mitochondrial fractions of human fibroblasts and liver tissue. An even cytosolic distribution with an intense perinuclear decoration of GLUT10 was demonstrated by immunofluorescence in human fibroblasts, whilst mitochondrial markers revealed a fully different decoration pattern. GLUT10 decoration was fully absent in fibroblasts from three ATS patients. Expression of exogenous, tagged GLUT10 in fibroblasts from an ATS patient revealed a strict co-localization with the ER marker protein disulfide isomerase (PDI). The results demonstrate that GLUT10 is present in the ER. [ABSTRACT FROM AUTHOR]

Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite numerous research efforts, no causative gene(s) or validated biomarkers have been identified and insights into the disease-causing mechanisms remain scarce. Variability in the spectrum and severity of symptoms and progression of hEDS patients' phenotype likely depend on a combination of age, gender, lifestyle, and the probable multitude of genes involved in hEDS. However, considering the clinical overlap with other EDS forms, which lead to abnormalities in extracellular matrix (ECM), it is plausible that the mechanisms underlying hEDS pathogenesis also affect the ECM to a certain extent. Herein, we performed a series of in vitro studies on the secretome of hEDS dermal fibroblasts that revealed a matrix metalloproteinases (MMPs) dysfunction as one of the major disease drivers by causing a detrimental feedback loop of excessive ECM degradation coupled with myofibroblast differentiation. We demonstrated that doxycycline-mediated inhibition of MMPs rescues in hEDS cells a control-like ECM organization and induces a partial reversal of their myofibroblast-like features, thus offering encouraging clues for translational studies confirming MMPs as a potential therapeutic target in hEDS with the expectation to improve patients' quality of life and alleviate their disabilities. [ABSTRACT FROM AUTHOR]

Ehlers–Danlos syndromes (EDS) are a group of heritable connective tissue disorders (HCTDs) characterized by a variable degree of skin hyperextensibility, joint hypermobility and tissue fragility. The current EDS classification distinguishes 13 subtypes and 19 different causal genes mainly involved in collagen and extracellular matrix synthesis and maintenance. EDS need to be differentiated from other HCTDs with a variable clinical overlap including Marfan syndrome and related disorders, some types of skeletal dysplasia and cutis laxa. Clinical recognition of EDS is not always straightforward and for a definite diagnosis, molecular testing can be of great assistance, especially in patients with an uncertain phenotype. Currently, the major challenging task in EDS is to unravel the molecular basis of the hypermobile EDS that is the most frequent form, and for which the diagnosis is only clinical in the absence of any definite laboratory test. This EDS subtype, as well as other EDS-reminiscent phenotypes, are currently investigated worldwide to unravel the primary genetic defect and related pathomechanisms. The research articles, case report, and reviews published in this Special Issue focus on different clinical, genetic and molecular aspects of several EDS subtypes and some related disorders, offering novel findings and future research and nosological perspectives. [ABSTRACT FROM AUTHOR]

The Ehlers-Danlos syndromes (EDS) constitute a clinically and genetically heterogeneous group of connective tissue disorders. Tenascin X (TNX) deficiency is a rare type of EDS, defined as classical-like EDS (clEDS), since it phenotypically resembles the classical form of EDS, though lacking atrophic scarring. Although most patients display a well-defined phenotype, the diagnosis of TNX-deficiency is often delayed or overlooked. Here, we described an additional patient with clEDS due to a homozygous null-mutation in the TNXB gene. A review of the literature was performed, summarizing the most important and distinctive clinical signs of this disorder. Characterization of the cellular phenotype demonstrated a distinct organization of the extracellular matrix (ECM), whereby clEDS distinguishes itself from most other EDS subtypes by normal deposition of fibronectin in the ECM and a normal organization of the α5β1 integrin. [ABSTRACT FROM AUTHOR]

Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-β pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management. [ABSTRACT FROM AUTHOR]

Two probands are reported with pathogenic and likely pathogenic COL5A1 variants (frameshift and splice site) in whom no collagen flowers have been identified with transmission electron microscopy (TEM). One proband fulfils the clinical criteria for classical Ehlers-Danlos syndrome (cEDS) while the other does not and presents with a vascular complication. This case report highlights the significant intrafamilial variability within the cEDS phenotype and demonstrates that patients with pathogenic COL5A1 variants can have an absence of collagen flowers on TEM skin biopsy analysis. This has not been previously reported in the literature and is important when evaluating the significance of a TEM result in patients with clinically suspected cEDS and underscores the relevance of molecular analysis. [ABSTRACT FROM AUTHOR]

The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives. [ABSTRACT FROM AUTHOR]

The Ehlers‒Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and extracellular matrix (ECM) biology. Classical (cEDS), vascular (vEDS), and hypermobile (hEDS) EDS are the most frequent types. cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown. For these disorders, the molecular pathology remains poorly studied. Herein, we review, expand, and compare our previous transcriptome and protein studies on dermal fibroblasts from cEDS, vEDS, and hEDS patients, offering insights and perspectives in their molecular mechanisms. These cells, though sharing a pathological ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum homeostasis, autophagy, and wound healing are perturbed. In hEDS cells, gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of the disorder. Finally, emerging findings from miRNA profiling of hEDS fibroblasts are discussed to add some novel biological aspects about hEDS etiopathogenesis. [ABSTRACT FROM AUTHOR]

Ehlers-Danlos syndrome (EDS) comprises clinically heterogeneous connective tissue disorders with diverse molecular etiologies. The 2017 International Classification for EDS recognized 13 distinct subtypes caused by pathogenic variants in 19 genes mainly encoding fibrillar collagens and collagen-modifying or processing proteins. Recently, a new EDS subtype, i.e., classical-like EDS type 2, was defined after the identification, in six patients with clinical findings reminiscent of EDS, of recessive alterations in AEBP1, which encodes the aortic carboxypeptidase–like protein associating with collagens in the extracellular matrix. Herein, we report on a 53-year-old patient, born from healthy second-cousins, who fitted the diagnostic criteria for classical EDS (cEDS) for the presence of hyperextensible skin with multiple atrophic scars, generalized joint hypermobility, and other minor criteria. Molecular analyses of cEDS genes did not identify any causal variant. Therefore, AEBP1 sequencing was performed that revealed homozygosity for the rare c.1925T>C p.(Leu642Pro) variant classified as likely pathogenetic (class 4) according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The comparison of the patient's features with those of the other patients reported up to now and the identification of the first missense variant likely associated with the condition offer future perspectives for EDS nosology and research in this field. [ABSTRACT FROM AUTHOR]