The Ehlers‐Danlos syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. There is phenotypic and ...genetic variation among the 13 subtypes. The initial genetic findings on EDS were related to alterations in fibrillar collagen, but the elucidation of the molecular basis of many of the subtypes revealed several genes not involved in collagen biosynthesis or structure. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several comorbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on age, gender, lifestyle, and expression domains of the EDS genes during development and postnatal life. In this review, we summarize the current molecular, genetic, epidemiologic, and pathogenetic findings related to EDS with a focus on the hypermobile type.
Key Findings
A comprehensive review of EDS phenotypes, diagnoses and causes with a focus on the hESD subtype
Will serve as a critical resource for the connective tissue community
Displays expression of many of the EDS genes during development
Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy ...bruising, and generalized joint hypermobility. It comprises Ehlers-Danlos syndrome type I and Ehlers-Danlos syndrome type II, but it is now apparent that these form a continuum of clinical findings and differ only in phenotypic severity. It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2-chain of type V collagen, respectively. However, because no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined patient group, this number may underestimate the real proportion of patients with classic Ehlers-Danlos syndrome harboring a mutation in one of these genes. In the majority of patients with molecularly characterized classic Ehlers-Danlos syndrome, the disease is caused by a mutation leading to a nonfunctional COL5A1 allele and resulting in haploinsufficiency of type V collagen. A smaller proportion of patients harbor a structural mutation in COL5A1 or COL5A2, causing the production of a functionally defective type V collagen protein. Most mutations identified so far result in a reduced amount of type V collagen in the connective tissues available for collagen fibrillogenesis. Inter- and intrafamilial phenotypic variability is observed, but no genotype-phenotype correlations have been observed. No treatment for the underlying defect is presently available for Ehlers-Danlos syndrome. However, a series of preventive guidelines are applicable.
Cardiovascular system involvements have been frequently reported in hypermobile Ehlers‐Danlos Syndrome (hEDS). Mitral valve prolapse (MVP) and aortic root dilatation are included in the 2017 ...international classification criteria for hEDS. Different studies have found conflicting results regarding the significance of cardiac involvement in hEDS patients. We conducted a retrospective review of cardiac involvement in patients diagnosed with hEDS based on the 2017 International diagnostic criteria to provide further evidence toward more defined and reliable diagnostic criteria and recommended cardiac surveillance. A total of 75 hEDS patients with at least one diagnostic cardiac evaluation were included in the study. The most common reported cardiovascular complaints were lightheadedness (80.6%), followed by palpitations (77.6%), fainting (44.8%), and chest pain (32.8%). Of the 62 echocardiogram reports, 57 (91.9%) showed trace/trivial to mild valvular insufficiency, and 13 (21%) had additional abnormalities such as grade I diastolic dysfunction, mild aortic sclerosis, and trivial or small pericardial effusion. Of the 60 electrocardiograms (ECG) reports, 39 (65%) were normal, and 21 (35%) reported minor abnormalities or normal variants. Even though many hEDS patients in our cohort experienced cardiac symptoms, the presence of a significant cardiac abnormality was very low.
The genomic region surrounding the Tenascin‐XB gene (TNXB) is a complex and duplicated region, with several pseudogenes that predispose to high rates of homologous recombination. Classical‐like ...Ehlers–Danlos syndrome (clEDS) is the result of tenascin‐X deficiency due to biallelic loss of function variants in the TNXB gene. Here we present a patient with clEDS and spontaneous pneumothorax, a feature not previously reported to be associated with this condition. Two inherited pathogenic/likely pathogenic variants were identified; a previously reported deletion resulting in a TNXA/TNXB chimeric gene and a novel frameshift variant. The Tenascin‐XB gene is well described in the literature to be associated with collagen metabolism, stabilization of the fibrillar‐collagen matrix and is expressed abundantly in the extracellular matrix. We propose that tenascin‐X deficiency is directly related to pneumothorax predisposition. This case expands the phenotypic spectrum of clEDS and highlights the challenges with molecular analysis and diagnosis
The UK National Diagnostic Service for Ehlers-Danlos Syndromes (EDS) was established in 2009 for the rare types of EDS. Vascular EDS (vEDS) is an inherited connective tissue disorder caused by ...pathogenic variants in the COL3A1 gene. Associated tissue fragility affects multiple organ systems, increasing the risk of blood vessel dissection and rupture, with potentially fatal consequences. The diagnosis of vEDS has improved with advances in genetic testing, however this is most often suspected following an acute event. We provide data on the clinical features of vEDS for 180 patients (full cohort) seen in our service with confirmed molecular diagnoses. Increased awareness of this rare condition will prompt genetic testing essential to confirm the diagnosis. Outcomes are improved by early diagnosis followed by appropriate management. Fragile connective tissues make invasive procedures potentially dangerous, particularly in an emergency setting. Lifestyle advice from a young age can help acceptance and understanding of the diagnosis and inform choices. There is currently limited evidence for the use of drug therapy to reduce vascular events. We report on the incidence of vascular events in 126 patients (statistical analysis cohort) in our care and the use of medication. Our retrospective data showed that those patients on a long-term angiotensin II receptor blocker and/or beta-blocker had fewer vascular events than those not on cardiac medication who received the same lifestyle and emergency care advice.
Type III collagen is a major fibrillar collagen consisting of three identical α1(III)-chains that is particularly present in tissues exhibiting elastic properties, such as the skin and the arterial ...wall. Heterozygous mutations in the COL3A1 gene result in vascular Ehlers-Danlos syndrome (vEDS), a severe, life-threatening disorder, characterized by thin, translucent skin and propensity to arterial, intestinal and uterine rupture. Most human vEDS cases result from a missense mutation substituting a crucial glycine residue in the triple helical domain of the α1(III)-chains. The mechanisms by which these mutant type III collagen molecules cause dermal and vascular fragility are not well understood. We generated a transgenic mouse line expressing mutant type III collagen, containing a typical helical glycine substitution (p.(Gly182Ser)). This Col3a1Tg-G182S mouse line displays a phenotype recapitulating characteristics of human vEDS patients with signs of dermal and vascular fragility. The Col3a1Tg-G182S mice develop severe transdermal skin wounds, resulting in early demise at 13–14weeks of age. We found that this phenotype was associated with a reduced total collagen content and an abnormal collagen III:I ratio, leading to the production of severely malformed collagen fibrils in the extracellular matrix of dermal and arterial tissues. These results indicate that expression of the glycine substitution in the α1(III)-chain disturbs formation of heterotypic type III:I collagen fibrils, and thereby demonstrate a key role for type III collagen in collagen fibrillogenesis in dermal and arterial tissues.
•Mutant Col3a1 transgenic mouse model displays phenotype recapitulating human vascular EDS with signs of dermal and vascular fragility.•Type III collagen plays a key role in collagen fibrillogenesis during dermal and arterial development.•Col3a1 transgenic mouse model provides tool for exploration of role of abnormal collagen III in fibrillogenesis and vascular EDS.
PDF
