Manejo odontológico de pacientes con el síndrome de Ehlers-Danlos: revisión narrativa / Dental management in patients with Ehlers-Danlos syndrome: a narrative review

El síndrome de Ehlers-Danlos es una enfermedad heredita- ria, producida por mutaciones cromosómicas que pueden llegar a tener un comportamiento autosómico dominante, recesivo o ligado al cromosoma X. Se caracteriza por defectos en las enzi- mas encargadas de la estructura y síntesis de colágeno. En vista de los 20 tipos de colágeno que existen, este síndrome es extre- madamente heterogéneo tanto en su presentación clínica como en su progresión y evolución. Dentro de los signos y síntomas habituales encontramos la hiperlaxitud articular, hiperelastici- dad de la piel e hiperequimosis de los vasos sanguíneos. Con relación a las complicaciones que pueden presentar es- tos pacientes, encontramos dislocaciones articulares, fragilidad en la piel, dolor articular, ruptura de grandes vasos sanguíneos, dificultad en la cicatrización y, en consecuencia, mayor inci- dencia de procesos infecciosos y de cicatrices poco estéticas. Presenta una incidencia de 1 caso cada 2.500-5.000 na- cidos vivos. Por ello, es fundamental que el odontólogo se encuentre familiarizado con el manejo médico-dental de estos pacientes, a fin de estar preparado para brindarles un trata- miento adecuado y responder ante las posibles complicacio- nes que se pueden presentar. En esta revisión se emplearon resultados extraídos manual- mente de artículos, indexados en las bases de datos PUBMED y EBSCO, que respondían a la búsqueda de los términos Ehlers-Danlos syndrome, dental management y oral surgery. El objetivo fue describir el manejo médico-odontológico del paciente con síndrome de Ehlers-Danlos hasta la fecha (AU)

Ehlers-Danlos syndrome is a hereditary disease, produced by chromosomal mutations that can have an autosomal behavior, which can be dominant, recessive or X-linked. It is characterized by defects in the enzymes responsible for the structure and syn- thesis of collagen. In view of the 20 existent types of collagen, this syndrome is extremely heterogeneous in its clinical presentation, as well as in its progression and evolution. Within the usual signs and symptoms, we find joint hyperlaxity, skin hyperelasticity and hyper-ecchymosis of the blood vessels. Regarding the complications that these patients can pres- ent, we find joint dislocations, skin fragility, joint pain, rupture of large blood vessels, difficulty in healing and, consequently, a higher incidence of infectious processes and unsightly scars. It presents an incidence of 1 case every 2.500-5.000 live births. Therefore, it is essential that the dentist is familiar with the medical-dental management of these patients, in order to be prepared to provide them with adequate treatment and re- spond to possible complications that may arise. In this review, results were manually extracted from ar- ticles, indexed in the PUBMED and EBSCO databases, that respond to the search for the terms Ehlers-Danlos syndrome, dental management and oral surgery. The aim was describing the medical-dental management of patients with Ehlers-Dan- los syndrome to date (AU)

Molecular Genetics and Pathogenesis of Ehlers-Danlos Syndrome and Related Connective Tissue Disorders.

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.

A review of Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) describes a group of heritable disorders of connective tissue comprising mutations in the genes involved in the structure and/or biosynthesis of collagen. Thirteen EDS subtypes are recognized, with a wide degree of symptom overlap among subtypes and with other connective tissue disorders. The clinical hallmarks of EDS are tissue fragility, joint hypermobility, and skin hyperextensibility. Appropriate diagnosis of EDS is important for correct multidisciplinary management and is associated with better clinical outcomes for patients.

COL1-related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers-Danlos syndrome overlap.

The 2017 classification of Ehlers-Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re-define this OI/EDS overlap as a missing EDS type. Twenty-one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS-related features. OI-related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N-proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.

Symptomatic Joint Hypermobility: The Hypermobile Type of Ehlers-Danlos Syndrome and the Hypermobility Spectrum Disorders.

Joint hypermobility may be syndromic or nonsyndromic, asymptomatic or symptomatic. However, asymptomatic joint hypermobility can cause repetitive use injury, alter biomechanics, or become symptomatic later in life. Symptomatic joint hypermobility can result from soft tissue injury or muscular strain caused by muscular imbalance. Treatment is straightforward once joint hypermobility is recognized. Generalized joint hypermobility can be assessed using a standardized in-office examination. Generalized joint hypermobility may also be a feature of a heritable connective tissue disorder with other systemic findings. Therefore, assessing joint hypermobility in the context of musculoskeletal complaints may lead to recognizing systemic manifestations and allow treatment accordingly.

An update on the new classification of Ehlers-Danlos syndrome and review of the causes of bleeding in this population.

It has long been hypothesized that bleeding symptoms in people with hypermobility occur as a result of abnormalities in the collagen of the vessel wall or the connective tissues. The bleeding symptoms, particularly in the skin, have been attributed to the fragility of skin and blood vessels caused by "defective collagen wickerwork" of the reticular layer of the skin. Collagen, which forms the framework of vessel walls, is altered in many patients with Ehlers-Danlos syndrome (EDS) leading to weakening of the vessel wall or the supporting tissues. Another important function of subendothelial collagen is its interaction with platelets and von Willebrand factor, which results in the propagation of a platelet plug. Thus, abnormalities in subendothelial collagen may alter its interaction with platelets and VWF. More recently, hypermobile-EDS (hEDS) has been associated with mast cell disorders, a condition independently associated with bleeding symptoms. It has also been observed that patients with mild bleeding disorders have a more severe bleeding phenotype when they have co-existing joint hypermobility.

[Up-to-date classification and multidisciplinary symptoms of Ehlers-Danlos syndromes]. / Az Ehlers­Danlos-szindrómák korszeru osztályozása és multidiszciplináris tünettana.

In this review article, the authors summarize the clinical aspects of the novel classification of Ehlers-Danlos syndrome, which is a group of rare, hereditary connective tissue disorders. The leading symptom of the Ehlers-Danlos syndrome group is joint hypermobility, skin hyperextensibility and generalized tissue fragility. Ehlers-Danlos syndrome displays a high clinical and genetic heterogeneity and harbors many multidisciplinary properties. Certain subtypes only affect the quality of life, while other forms may lead to severe, even fatal vascular or intestinal complications. Last year, based on the data of various international genotype-phenotype correlation studies of large populations, a new classification of the syndrome's clinical subtypes was introduced. The novel international nosology of Ehlers-Danlos syndromes published in 2017 delineates 13 clinical subtypes, describes their genetic background and defines major and minor diagnostic criteria for each subtype. We gathered the complex, multidisciplinary symptoms of Ehlers-Danlos syndromes in a table to assist the diagnosis from a differential diagnostic point of view. In the clinical practice, the proper diagnosis of patients affected by the Ehlers-Danlos syndrome group is essential to give optimal clinical care and to prevent the development of severe complications. Orv Hetil. 2019; 160(16): 603-612.

Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers-Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility.

PURPOSE: The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance. METHODS: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed. RESULTS: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS. CONCLUSION: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.

Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients.

OBJECTIVES: This study is aimed at identifying discrete severity classes among adults with hypermobile Ehlers-Danlos syndrome (hEDS)/hypermobility spectrum disorders (HSD). METHODS: Subjects were selected according to the old and new nomenclatures and all completed a set of questionnaires exploring pain, fatigue, dysautonomic symptoms, coordination and attention/concentration deficits and quality of life in general. Data were investigated by hierarchical clustering on principal components. Cluster comparisons were then performed by using the two-sample unpaired t test and the standardized mean difference was reported as a measure of effect size. Conditional classification tree analysis and multivariable logistic regression were carried out in order to identify the profiles that were at higher risk to belong to the more severe cluster. Weighted linear combination was used to identify a numerical score measuring this risk. RESULTS: A total of 105 patients were selected and distributed in two distinct severity groups. These groups were statistically separated on the basis of 47 of 59 items/characteristics. One group featured the worse values of most questionnaire items (complex/severe cluster) and the other was dominated by the better values (simplex/milder cluster). Only three items were able to stratify patients according to their risk to belong to the complex cluster. A severity score was then constructed on these three items. CONCLUSION: Adults with hEDS/HSD can be separated in two severity classes, which do not mirror either the old or new criteria for hEDS. The identified severity score could allow a bi-dimensional approach to adults with hEDS/HSD for optimal management planning.

[Ehlers-Danlos syndromes]. / Les syndromes d'Ehlers-Danlos.

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inheritable connective tissue disorders characterized by skin hyperextensibility, joint hypermobility and cutaneous fragility with delayed wound healing. Over and above these common features, they differ in the presence or absence of various organ and tissue abnormalities, and differences in genetic causal mechanisms and degree of severity. They are complex and multisystem diseases, with the majority being highly disabling because of major joint problems and neurosensory deficiencies, and in some cases, they may be life-threatening due to associated complications, especially vascular disorders. In 1997, the Villefranche classification defined 6 subtypes of EDS. However, many other new variants have been described over the last years. The "historical" EDS were characterized by abnormalities in fibrillar collagen protein synthesis. More recently, disorders of synthesis and organization of the extracellular matrix have been shown to be responsible for other types of EDS. Thus, many EDS are in fact metabolic diseases related to enzymatic defects. While there is no curative treatment for any type of EDS, early diagnosis is of utmost importance in order to optimize the symptomatic management of patients and to prevent avoidable complications. Patients must be treated and monitored by multidisciplinary teams in highly specialized reference centers. In this article, we present the current state of knowledge on these diseases that continue to be elucidated thanks to new molecular genetic techniques.

Postural tachycardia in hypermobile Ehlers-Danlos syndrome: A distinct subtype?

INTRODUCTION: It is not clear if patients with postural tachycardia syndrome (POTS) and Ehlers-Danlos syndrome (hEDS) differ from patients with POTS due to other etiologies. We compared the results of autonomic testing and healthcare utilization in POTS patients with and without hEDS. METHODS: Patients with POTS+hEDS (n=20) and POTS controls without hypermobility (n=20) were included in the study. All patients underwent autonomic testing, and the electronic medical records were reviewed to determine the number and types of medications patients were taking, as well as the number of outpatient, emergency department, and inpatient visits over the prior year. RESULTS: Patients with hEDS had twice as many outpatient visits (21 v. 10, p=0.012), were taking more prescription medications (8 vs. 5.5, p=0.030), and were more likely to see a pain physician (70% vs 25%, p=0.005). Autonomic testing demonstrated a slight reduction in heart rate variability and slightly lower blood pressures on tilt table testing in hEDS patients, however for most patients these variables remained within the range of normal. Orthostatic tachycardia on tilt table testing was greater in POTS controls (46bpm vs 39bpm, p=0.018). Abnormal QSweat responses were common in both groups (38% of POTS+hEDS and 36% of POTS controls). CONCLUSIONS: While autonomic testing results were not significantly different between groups, patients with POTS+hEDS took more medications and had greater markers of healthcare utilization, with chronic pain likely playing a prominent role.

The Ehlers-Danlos syndromes, rare types.

The Ehlers-Danlos syndromes comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders, which are characterized by joint hypermobility, skin hyperextensibility, and tissue friability. In the Villefranche Nosology, six subtypes were recognized: The classical, hypermobile, vascular, kyphoscoliotic, arthrochalasis, and dermatosparaxis subtypes of EDS. Except for the hypermobile subtype, defects had been identified in fibrillar collagens or in collagen-modifying enzymes. Since 1997, a whole spectrum of novel, clinically overlapping, rare EDS-variants have been delineated and genetic defects have been identified in an array of other extracellular matrix genes. Advances in molecular testing have made it possible to now identify the causative mutation for many patients presenting these phenotypes. The aim of this literature review is to summarize the current knowledge on the rare EDS subtypes and highlight areas for future research. © 2017 Wiley Periodicals, Inc.

The 2017 international classification of the Ehlers-Danlos syndromes.

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.

Ehlers-Danlos syndrome, classical type.

Classical EDS is a heritable disorder of connective tissue. Patients are affected with joint hypermobility, skin hyperextensibilty, and skin fragility leading to atrophic scarring and significant bruising. These clinical features suggest consideration of the diagnosis which then needs to be confirmed, preferably by genetic testing. The most recent criteria for the diagnosis of EDS were devised in Villefranche in 1997. [Beighton et al. (1998); Am J Med Genet 77:31-37]. The aims set out in the Villefranche Criteria were: to enable diagnostic uniformity for clinical and research purposes, to understand the natural history of each subtype of EDS, to inform management and genetic counselling, and to identify potential areas of research. The authors recognized that the criteria would need updating, but viewed the Villefranche nosology as a good starting point. Since 1997, there have been major advances in the molecular understanding of classical EDS. Previous question marks over genetic heterogeneity have been largely surpassed by evidence that abnormalities in type V collagen are the cause. Advances in molecular testing have made it possible to identify the causative mutation in the majority of patients. This has aided the further clarification of this diagnosis. The aim of this literature review is to summarize the current knowledge and highlight areas for future research. © 2017 Wiley Periodicals, Inc.

Increased Need for Gastrointestinal Surgery and Increased Risk of Surgery-Related Complications in Patients with Ehlers-Danlos Syndrome: A Systematic Review.

BACKGROUND/AIMS: Ehlers-Danlos syndromes (EDSs) constitute a rare group of inherited connective tissue diseases, characterized by multisystemic manifestations and general tissue fragility. Most severe complications include vascular and gastrointestinal (GI) emergencies requiring acute surgery. The purpose of this systematic review was to assess the causes of GI-related surgery and related mortality and morbidity in patients with EDSs. METHODS: A systematic search was conducted in PubMed, Embase, and Scopus to identify relevant studies. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines for systematic reviews were followed. According to eligibility criteria, data were extracted and systematically screened by 2 authors. RESULTS: Screening process identified 11 studies with a total of 1,567 patients. Findings indicated that patients with EDSs had a higher occurrence of surgery demanding GI manifestations, including perforation, hemorrhage, rupture of intra-abdominal organs, and rectal prolapse. Most affected was the vascular subtype, of which up to 33% underwent GI surgery and suffered from a lowered average life expectancy of 48 years (range 6-78). Secondary complications of surgery were common in all patients with EDSs. CONCLUSION: Studies suggested that patients with EDSs present an increased need for GI surgery, but also an increased risk of surgery-related complications, most predominantly seen in the vascular subtype.

[Ehlers-Danlos syndrome].

Ehlers-Danlos syndrome (EDS) comprises a group of diseases characterized by connective tissue fragility. The clinical symptoms primarily involve the skin, joints, blood vessels and internal organs. Diagnosing EDS is complicated because of the clinical variability, imprecise diagnostic criteria, and because physicians may lack knowledge of this rare disease. The aim of this article is to provide an overview of the clinical symptoms and to provide recommendations on diagnosis and treatment. Referring patients to one of the national centres for rare diseases is important.

Ehlers Danlos syndrome and gastrointestinal manifestations: a 20-year experience at Mayo Clinic.

BACKGROUND: Gastrointestinal (GI) manifestations are found in Ehlers Danlos syndrome (EDS) hypermobility subtype (HM). We aimed to assess associations between EDS HM and other EDS subtypes with GI manifestations. METHODS: We reviewed medical records of EDS patients evaluated at Mayo Clinic's Medical Genetics Clinic 1994-2013. We extracted information regarding EDS subtypes, GI manifestations, and treatments. KEY RESULTS: We identified 687 patients; 378 (56%) had associated GI manifestations (female 86.8%, diagnosis mean age 29.6 years). Of the patients identified, 58.9% (43/73) had EDS classic, 57.5% (271/471) EDS HM, 47.3% (27/57) EDS vascular subtypes. In addition, 86 patients had EDS that could not be classified in any of those three subtypes. Commonest GI symptoms were: abdominal pain (56.1%), nausea (42.3%), constipation (38.6%), heartburn (37.6%), and irritable bowel syndrome-like symptoms (27.5%). Many GI symptoms were commoner in EDS HM than the other subtypes together. Among 37.8% of the 378 patients who underwent esophagogastroduodenoscopy, the commonest abnormalities were gastritis, hiatal hernia and reflux esophagitis. Abnormal gastric emptying was observed in 22.3% (17/76): 11.8% delayed and 10.5% accelerated. Colonic transit was abnormal in 28.3% (13/46): 19.6% delayed and 8.7% accelerated. Rectal evacuation disorder was confirmed in 18/30 patients who underwent anorectal manometry. Angiography showed aneurysms in abdominal vessels in EDS vascular type. Proton pump inhibitors (38%) and drugs for constipation (23%) were the most commonly used medications. A minority underwent colectomy (2.9%) or small bowel surgery (4%). CONCLUSIONS & INFERENCES: EDS HM and other subtypes should be considered in patients with chronic functional GI symptoms and abdominal vascular lesions.

Utilidad de la ecografía de alta frecuencia en el diagnóstico de las pápulas piezogénicas / Usefulness of High-Frequency Ultrasound in the Diagnosis of Piezogenic Pedal Papules

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Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia.

CONTEXT: The contiguous gene deletion syndrome (CAH-X) was described in a subset (7%) of congenital adrenal hyperplasia (CAH) patients with a TNXA/TNXB chimera, resulting in deletions of CYP21A2, encoding 21-hydroxylase necessary for cortisol biosynthesis, and TNXB, encoding the extracellular matrix glycoprotein tenascin-X (TNX). This TNXA/TNXB chimera is characterized by a 120-bp deletion in exon 35 and results in TNXB haploinsufficiency, disrupted TGF-ß signaling, and an Ehlers Danlos syndrome phenotype. OBJECTIVE: The objective of the study was to determine the genetic status of TNXB and resulting protein defects in CAH patients with a CAH-X phenotype but not the previously described TNXA/TNXB chimera. Design, Settings, Participants, and Intervention: A total of 246 unrelated CAH patients were screened for TNXB defects. Genetic defects were investigated by Southern blotting, multiplex ligation-dependent probe amplification, Sanger, and next-generation sequencing. Dermal fibroblasts and tissue were used for immunoblotting, immunohistochemical, and coimmunoprecipitation experiments. MAIN OUTCOME MEASURES: The genetic and protein status of tenascin-X in phenotypic CAH-X patients was measured. RESULTS: Seven families harbor a novel TNXB missense variant c.12174C>G (p.C4058W) and a clinical phenotype consistent with hypermobility-type Ehlers Danlos syndrome. Fourteen CAH probands carry previously described TNXA/TNXB chimeras, and seven unrelated patients carry the novel TNXB variant, resulting in a CAH-X prevalence of 8.5%. This highly conserved pseudogene-derived variant in the TNX fibrinogen-like domain is predicted to be deleterious and disulfide bonded, results in reduced dermal elastin and fibrillin-1 staining and altered TGF-ß1 binding, and represents a novel TNXA/TNXB chimera. Tenascin-X protein expression was normal in dermal fibroblasts, suggesting a dominant-negative effect. CONCLUSIONS: CAH-X syndrome is commonly found in CAH due to 21-hydroxylase deficiency and may result from various etiological mechanisms.