Hypermobile Ehlers-Danlos syndrome: A review and a critical appraisal of published genetic research to date.

The Ehlers-Danlos syndromes (EDS) are a collection of rare hereditary connective tissue disorders with heterogeneous phenotypes, usually diagnosed following clinical examination and confirmatory genetic testing. Diagnosis of the commonest subtype, hypermobile Ehlers-Danlos Syndrome (hEDS), relies solely on a clinical diagnosis since its molecular aetiology remains unknown. We performed an up-to-date literature search and selected 11 out of 304 publications according to a set of established criteria. Studies reporting variants affecting collagen proteins were found to be hindered by cohort misclassification and subsequent lack of reproducibility of these genetic findings. The role of the described variants affecting Tenascin-X and LZTS1 is yet to be demonstrated in the majority of hEDS cases, while the functional implication of associated signaling pathways and genes requires further elucidation. The available literature on the genetics of hEDS is scant, dispersed and conflicting due to out-dated nosology terminology. Recent literature has suggested the role of several promising candidate mechanisms which may be linked to the underlying molecular aetiology. Knowledge of the molecular genetic basis of hEDS is expected to increase in the near future through the mainstream use of high-throughput sequencing combined with the updated classification of EDS, and the upcoming Hypermobile Ehlers-Danlos Genetic Evaluation (HEDGE) study.

Periodontal (formerly type VIII) Ehlers-Danlos syndrome: Description of 13 novel cases and expansion of the clinical phenotype.

Periodontal Ehlers-Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early-onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non-invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.

Deconstructing and reconstructing joint hypermobility on an evo-devo perspective.

Joint hypermobility is a common characteristic in humans. Its non-casual association with various musculoskeletal complaints is known and currently defined "the spectrum". It includes hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). hEDS is recognized by a set of descriptive criteria, while HSD is the background diagnosis for individuals not fulfilling these criteria. Little is known about the aetiopathogenesis of the spectrum. It may be interpreted as a complex trait according to the integration model. Particularly, the spectrum is common in the general population, affects morphology, presents extreme clinical variability and is characterized by marked sex bias without a clear Mendelian or hormonal explanation. Joint hypermobility and the other hEDS systemic criteria are intended as qualitative derivatives of continuous traits of normal morphological variability. The need for a minimum set of criteria for hEDS diagnosis implies a tendency to co-vary of these underlying continuous traits. In evolutionary biology, such a co-variation (i.e. integration) is driven by multiple forces, including genetic, developmental, functional and environmental/acquired interactors. The aetiopathogenesis of the spectrum may be resolved by a deeper understanding of phenotypic variability, which superimposes on normal morphological variability.

Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes.

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.

High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers-Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia.

Many patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency have CAH-X syndrome, a connective tissue dysplasia consistent with hypermobility-type Ehlers-Danlos syndrome due to a contiguous gene deletion involving the adjacent CYP21A2 and TNXB genes. CAH-X syndrome is caused by carrying CYP21A1P-TNXA/TNXB chimeric genes [CAH-X chimera 1 (CH-1) and chimera 2 (CH-2)] on one or more alleles. Genetic analysis is cumbersome due to pseudogene interference. We developed a PCR-based CAH-X high-throughput screening method to assess the copy numbers of TNXB exons 35 and 40; this method is amenable to either real-time quantitative PCR or droplet digital PCR (ddPCR). The assay was validated in a cohort of 278 subjects from 146 unrelated CAH families. Results were confirmed by a validated Sanger sequencing platform. A total of 44 CAH-X-positive calls were made, with 42 (26 CH-1 and 16 CH-2) confirmed. The assay had 100% sensitivity (42 true/42 positives), 99.2% specificity (234 true/236 negatives), and an overall 99.3% accuracy (276/278). Calls made by real-time quantitative PCR and ddPCR were consistent (100%), and ddPCR offered easier data interpretation. The CAH-X prevalence was 15.6% (21/135 probands), higher than the previously estimated 8.5%, and was particularly high (29.2% or 21/72) in those with a 30-Kb deletion. This assay is suitable for high-throughput CAH-X screening, especially in subjects testing positive for CAH in neonatal screening.

Craniofacial abnormality with skeletal dysplasia in mice lacking chondroitin sulfate N-acetylgalactosaminyltransferase-1.

Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and plays an important part in organogenesis. To elucidate the roles of CS for craniofacial development, we analyzed the craniofacial morphology in CS N-acetylgalactosaminyltransferase-1 (T1) gene knockout (KO) mice. T1KO mice showed the impaired intramembranous ossification in the skull, and the final skull shape of adult mice included a shorter face, higher and broader calvaria. Some of T1KO mice exhibited severe facial developmental defect, such as eye defects and cleft lip and palate, causing embryonic lethality. At the postnatal stages, T1KO mice with severely reduced CS amounts showed malocclusion, general skeletal dysplasia and skin hyperextension, closely resembling Ehlers-Danlos syndrome-like connective tissue disorders. The production of collagen type 1 was significantly downregulated in T1KO mice, and the deposition of CS-binding molecules, Wnt3a, was decreased with CS in extracellular matrices. The collagen fibers were irregular and aggregated, and connective tissues were dysorganized in the skin and calvaria of T1KO mice. These results suggest that CS regulates the shape of the craniofacial skeleton by modulating connective tissue organization and that the remarkable reduction of CS induces hypoplasia of intramembranous ossification and cartilage anomaly, resulting in skeletal dysplasia.

Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (vEDS) is a dominantly inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII), which is the major expressed collagen in blood vessels and hollow organs. The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain that through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, characterized by fragility of soft connective tissues with arterial and organ ruptures. To shed lights into molecular mechanisms underlying vEDS, we performed gene expression profiling in cultured skin fibroblasts from three patients with different structural COL3A1 mutations. Transcriptome analysis revealed significant changes in the expression levels of several genes involved in maintenance of cell redox and endoplasmic reticulum (ER) homeostasis, COLLs folding and extracellular matrix (ECM) organization, formation of the proteasome complex, and cell cycle regulation. Protein analyses showed that aberrant COLLIII expression is associated with the disassembly of many structural ECM constituents, such as fibrillins, EMILINs, and elastin, as well as with the reduction of the proteoglycans perlecan, decorin, and versican, all playing an important role in the vascular system. Furthermore, the altered distribution of the ER marker protein disulfide isomerase PDI and the strong reduction of the COLLs-modifying enzyme FKBP22 are consistent with the disturbance of ER-related homeostasis and COLLs biosynthesis and post-translational modifications, indicated by microarray analysis. Our findings add new insights into the pathophysiology of this severe vascular disorder, since they provide a picture of the gene expression changes in vEDS skin fibroblasts and highlight that dominant negative mutations in COL3A1 also affect post-translational modifications and deposition into the ECM of several structural proteins crucial to the integrity of soft connective tissues.

The Expanding Clinical Spectrum of Extracardiovascular and Cardiovascular Manifestations of Heritable Thoracic Aortic Aneurysm and Dissection.

More than 30 heritable conditions are associated with thoracic aortic aneurysm and dissection (TAAD). Heritable syndromic conditions, such as Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome, have somewhat overlapping systemic features, but careful clinical assessment usually enables a diagnosis that can be validated with genetic testing. Nonsyndromic FTAAD can also occur and in 20%-25% of these probands mutations exist in genes that encode elements of the extracellular matrix, signalling pathways (especially involving transforming growth factor-ß), and vascular smooth muscle cytoskeletal and contractile processes. Affected individuals with either a syndromic presentation or isolated TAAD can have mutations in the same gene. In this review we focus on the genes currently known to have causal mutations for syndromic and isolated FTAAD and outline the range of associated extracardiovascular and cardiovascular manifestations with each.

Cutaneous asthenia (Ehlers-Danlos-like syndrome) of Burmese cats.

OF CASES: A 6-month-old Burmese kitten developed focal skin lesions following a routine ovariohysterectomy. These were eventually attributed to the patient struggling during catheter placement and induction of anaesthesia. The lesions were caused by fluid extravasation in the subcutis and ischaemic necrosis of the overlying dermis, giving rise to an eschar-like appearance. Such lesions have been seen previously in Burmese cats with cutaneous asthenia and it is thought that they arise due to poor collagenous support for dermal blood vessels. An increased skin extensibility index (>23%) supported a diagnosis of cutaneous asthenia (Ehlers-Danlos-like syndrome), which has been reported as an inherited condition of Burmese cats in Australia, New Zealand and Europe. An additional Burmese cat with cutaneous asthenia is presented in detail, with lifetime follow-up and further salient observations by the owner, a veterinarian. Photographs of three other affected Burmese cats are provided to illustrate the range of presentations encountered with this condition. All five affected cats were presented with eschars, atrophic alopecia and increased skin extensibility, while one cat also had skin ulcers. Routine histopathological examination, including use of special stains such as trichrome, was unhelpful in establishing the diagnosis. CLINICAL REVIEW: The clinical features of this genetic disease of Burmese cats are reviewed, especially in relation to the postulated 'vasculopathy' that gives rise to characteristic skin lesions. Long term management of this condition is discussed briefly.

Transforming growth factor-ß and inflammation in vascular (type IV) Ehlers-Danlos syndrome.

BACKGROUND: Vascular Ehlers-Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified >20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments. METHODS AND RESULTS: We studied inflammatory and transforming growth factor-ß (TGF-ß) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype-phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-ß1, TGF-ß2, monocyte chemotactic protein-1, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and leptin and decreased interleukin-8 versus controls. VEDS dermal fibroblasts secreted more TGF-ß2, whereas downstream canonical/noncanonical TGF-ß signaling was not different. Patients with COL3A1 exon skipping mutations had higher plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and VEDS probands had abnormally high plasma C-reactive protein versus affected patients identified through family members before any disease manifestations. Patients with VEDS had higher mean platelet volumes, suggesting increased platelet turnover because of ongoing vascular damage, as well as increased regional truncal adiposity. CONCLUSIONS: These findings suggest that VEDS is a systemic disease with a major inflammatory component. C-reactive protein is linked to disease state and may be a disease activity marker. No changes in downstream TGF-ß signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-ß1. Finally, we found a novel role for dysregulated TGF-ß2, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.

Structure of human peptidyl-prolyl cis-trans isomerase FKBP22 containing two EF-hand motifs.

The FK506-binding protein (FKBP) family consists of proteins with a variety of protein-protein interaction domains and versatile cellular functions. It is assumed that all members are peptidyl-prolyl cis-trans isomerases with the enzymatic function attributed to the FKBP domain. Six members of this family localize to the mammalian endoplasmic reticulum (ER). Four of them, FKBP22 (encoded by the FKBP14 gene), FKBP23 (FKBP7), FKBP60 (FKBP9), and FKBP65 (FKBP10), are unique among all FKBPs as they contain the EF-hand motifs. Little is known about the biological roles of these proteins, but emerging genetics studies are attracting great interest to the ER resident FKBPs, as mutations in genes encoding FKBP10 and FKBP14 were shown to cause a variety of matrix disorders. Although the structural organization of the FKBP-type domain as well as of the EF-hand motif has been known for a while, it is difficult to conclude how these structures are combined and how it affects the protein functionality. We have determined a unique 1.9 Å resolution crystal structure for human FKBP22, which can serve as a prototype for other EF hand-containing FKBPs. The EF-hand motifs of two FKBP22 molecules form a dimeric complex with an elongated and predominantly hydrophobic cavity that can potentially be occupied by an aliphatic ligand. The FKBP-type domains are separated by a cleft and their putative active sites can catalyze isomerazation of two bonds within a polypeptide chain in extended conformation. These structural results are of prime interest for understanding biological functions of ER resident FKBPs containing EF-hand motifs.

The heart and pediatric rheumatology.

Recent advances in Kawasaki disease have included attempts to define genes involved in its pathogenesis. There have been recent advances in the studies of rheumatic carditis, leading to a better understanding of the mechanism of the disease. Histologic evaluation of patients with neonatal lupus erythematosus has revealed fibrosis with collagen deposition and calcification of the atrioventricular node. Therapy for cardiac involvement in systemic juvenile idiopathic arthritis should involve treatment of the underlying disease and systemic inflammatory state, and typically includes nonsteroidal antiinflammatory drugs, corticosteroids, disease-modifying drugs, and biologic therapies targeting tumor necrosis factor-alpha, interleukin-1, and interleukin-6.

Are we ignoring the dilated thoracic aorta?

The pathophysiology of thoracic aortic aneurysm (TAA) formation involves a complex interplay of genetic predisposition, cardiovascular risk factors, and hemodynamic forces. The medical community has resorted to the use of pharmacologic agents based on weak data transplanted from either abdominal aortic aneurysms (AAAs) or Marfan syndrome. However, aneurysms differ significantly based on their anatomic location and etiology. Epidemiologic and experimental data demonstrate that different genetic and nongenetic risk factors as well as diverse physiologic processes are responsible for the development and progression of sporadic TAA, familial TAA, and AAA. Therefore, these disease processes need to be considered as distinct entities and not hastily grouped together. The extrapolation of data from one aneurysmal disease process to another is still ill-founded and potentially harmful. Clinical trials in TAA are required before medical therapies, such as ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, or macrolide antibiotics, can be recommended.

Peoría paradójica en fístulas carótido-cavernosas durales: cuando el cuerpo se enferma más para curarse / Paradoxical worsening in carotid-cavemous ductal fistulas: when the body get more sick in order to cure

Las fístulas carótido-cavernosas son comunicaciones arteriovenosas patológicas entre la arteria carótida interna intravenosa y el seno venoso-cavernoso que la rodea. Un sistema de flujo y presión elevados irrumpe sobre otro de bajo flujo y velocidad. Ello origina los síntomas y signos. La gran mayoría, son resultantes de traumatismos craneales siendo de alto flujo y alta velocidad-fístulas traumáticas o directas; menos comunes son las llamadas fístulas espontáneas o durales localizadas en la duramadre y alimentadas por ramas menígeas provenientes de las arterías carótidas externa, interna o ambas y de las arterias vertebrales. Estas últimas raras veces tienen implicaciones graves para la vida, pero la pérdida visual constituye el mayor riesgo; no obstante, con elevada frecuencia, ocurre la oclusión espontánea, por lo que se impone la observación hasta que la sintomatología justifique el tratamiento. En el curso evolutivo puede ocurrir la trombosis aguda de la fístula y más propiamente de la totalidad de la vena oftálmica superior la que produce un distintivo cuadro de notable agravamiento de los síntomas que en forma contradictoria ocurre antes de la mejoría y reversión de los síntomas, el síndrome de empeoramiento o peoría paradójica. Para ilustrar el síndrome se presentan los casos clínicos de los pacientes

Caroid-cavernous fistulas are pathological arteriovenous communications between the intracavernous internal carotid artery and the cavernous sinus. A system of high flow and pressure bursts over another system of low flow and slow velocity. This causes the symptoms and signs. The vast majority are related with head trauma being high flow and high speed fistulas: traumatic or direct. Less common are the so-called spontaneous or dural fistulas located in the duramater and fed by meningeal branches from the external, internal, or both carotic arteries and the vertebral arteries. These latest rarely have serious implications for life, but visual loss is the greatest risk; however, with high frequency spontaneously occlusion occurs, and then observation imposes until symptoms justified the treatment. During its evolution acute thrombosis of the fistula itself can occur along the entire length of the ophthalmic vein which produces a distinctive and paradoxical worserning and reversal of symptoms, which is called the syndrome of paradoxical worserning. Clinical cases of two patients are presented to illustrate the syndrome

Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients.

Hypermobility type Ehlers-Danlos syndrome (HT-EDS) is a relatively frequent, although commonly misdiagnosed variant of Ehlers-Danlos syndrome, mainly characterized by marked joint instability and mild cutaneous involvement. Chronic pain, asthenia, and gastrointestinal and pelvic dysfunction are characteristic additional manifestations. We report on 21 HT-EDS patients selected from a group of 40 subjects with suspected mild hereditary connective tissue disorder. General, mucocutaneous, musculoskeletal, cardiovascular, neurologic, gastrointestinal, urogynecological, and ear-nose-throat abnormalities are investigated systematically and tabulated. Six distinct clinical presentations of HT-EDS are outlined, whose tabulation is a mnemonic for the practicing clinical geneticist in an attempt to diagnose this condition accurately. With detailed clinical records and phenotype comparison among patients of different ages, the natural history of the disorder is defined. Three phases (namely, hypermobility, pain, and stiffness) are delineated based on distinguishing manifestations. A constellation of additional, apparently uncommon abnormalities is also identified, including dolichocolon, dysphonia, and Arnold-Chiari type I malformation. Their further investigation may contribute to an understanding of the pathogenesis of the protean manifestations of HT-EDS, and a more effective approach to the evaluation and management of affected individuals.

Síndrome de Ehlers-Danlos: presentación de un caso / Ehlers-Danlos syndrome: presentation of a case

En este trabajo se realizó la presentación de un caso afectado con el Síndrome de Ehlers- Danlos, identificado en la consulta de Genética Clínica. Teniendo en cuenta la importancia y severidad de algunas de sus formas, y que el diagnóstico, en ocasiones, de las formas más leves no se realiza, se revisó la bibliográfica actualizada sobre esta patología para la mejor comprensión del caso(AU)

We present a case of a patient affected by the Ehlers-Danlos syndrome, identified at the Genetic Clinic consultation. Taking into account the importance and severity of some of its forms, and that sometimes the mildest forms are not diagnosed, we carried out an up-dated bibliographic review on this pathology for a better comprehension of the case(AU)

Síndrome de Ehlers-Danlos: presentación de un caso / Ehlers-Danlos syndrome: presentation of a case

En este trabajo se realizó la presentación de un caso afectado con el Síndrome de Ehlers- Danlos, identificado en la consulta de Genética Clínica. Teniendo en cuenta la importancia y severidad de algunas de sus formas, y que el diagnóstico, en ocasiones, de las formas más leves no se realiza, se revisó la bibliográfica actualizada sobre esta patología para la mejor comprensión del caso.

We present a case of a patient affected by the Ehlers-Danlos syndrome, identified at the Genetic Clinic consultation. Taking into account the importance and severity of some of its forms, and that sometimes the mildest forms are not diagnosed, we carried out an up-dated bibliographic review on this pathology for a better comprehension of the case.