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![Patient displays extreme hyperflexibility as represented by bilateral positive thumb to wrist signs on the Beighton hyperflexibility scale [6]. Raynaud's phenomenon of the fingers with cool temperature and decreased blood flow.](publication/316098917/figure/fig1/AS:573843557552129@1513826373698/Patient-displays-extreme-hyperflexibility-as-represented-by-bilateral-positive-thumb-to.png)
Patient displays extreme hyperflexibility as represented by bilateral positive thumb to wrist signs on the Beighton hyperflexibility scale [6]. Raynaud's phenomenon of the fingers with cool temperature and decreased blood flow.
Source publication
We report a 28-year-old female who presented with severe joint pain, chronic muscle weakness, Raynaud’s phenomenon, and hypermobility. She was found to have a 6074A > T nucleotide transition in the TNXB gene causing an amino acid protein change at Asp2025Val classified as likely pathogenic. We add this clinical report to the literature and classica...
Contexts in source publication
Context 1
... the clinic visit, we completed an assessment of the patient's joint mobility using the Beighton scale [6] , which results in a numerical score from 0 to 9 with one point assigned for the ability to perform each of the following actions: Passive dorsiflexion of the little finger beyond 90 degrees; passive apposition of the thumb to the flexor aspects of the forearm; hyperextension of the elbow beyond 10 degrees; hyperextension of the knee beyond 10 degrees; and forward flexion of the trunk, with knees straight, so that palms of hands rest easily on the floor. Our patient's Beighton score was 6 out of 9, including easy placement of palms to the floor (one point), hyperextension of both knees (two points), hyperextension of one elbow (one point), and passive apposition of both thumbs to the forearms (two points) as shown in Figure 1. ...
Context 2
... our patient also experienced Raynaud's phenomenon, manifested as paresthesia with decreased blood flow in her fingers, lip, ears, and nose ( Figure 1). This clinical presentation led to rheumatology evaluation including antibody studies and SED rate to diagnose a mixed connective tissue disorder such as lupus or rheumatoid arthritis. ...
Similar publications
Objective
Joint hypermobility in Ehlers‐Danlos Syndromes (EDS) predisposes persons with EDS to frequent subluxations and dislocations, chronic arthralgia, and soft‐tissue rheumatism. Epidemiologic trends of rheumatologic conditions among persons with EDS are lacking. Prescription claims databases can reflect underlying disease burdens by using medi...
Citations
... The diagnosis may be revised from hypermobile to classic when the individual's later development trends more towards cEDS, i.e. significant skin and soft tissue manifestations. In some cases with hEDS, a definitive genetic mutation on Tenascin XB has been found that manifests symptoms similar to cEDS [50]. However, there is no confirmation genetic test regarding hEDS; thus, the new EDS classification system in 2017 purposed to identify hEDS with a higher precision clinically. ...
The aim of this study was to assess the received TMD treatment modalities and the perceived outcome among the frequent types of EDS. A digital questionnaire was sent to the member of the National Swedish EDS Association during January-March 2022. The subsamples of hypermobile and classical EDS were constructed. Almost 90% reported TMD symptoms. Bite splint therapy, counselling, jaw training and occlusal adjustment were reported as the most common treatments with no statistically significant difference in terms of good effect between the two subsamples. Hypermobile and classical EDS might consider as an entity with regards to TMD.
... HCTDs include various syndromes with known genetic causes like Marfan syndrome [5], osteogenesis imperfecta [6], Melnick-Needles syndrome [7], cutis laxa [8], thoracic aortic aneurysms [9], and Ehlers-Danlos syndrome (EDS) [10]. Continued advancements in next-generation sequencing (NGS) over the past decade have facilitated the discovery of numerous genetic variants implicated in a variety of HCTDs [11][12][13]. For example, the genetic basis of 13 reported subtypes of EDS-classical (OMIM: 130000, 130010), classical-like (OMIM: 606408), cardiac-valvular (OMIM: 225320), vascular (OMIM: 130050), hypermobile (OMIM: 130020), arthrochalasia (OMIM: 130060), Dermatosparaxic (OMIM: 225410), kyphoscoliotic (OMIM: 225400, 614557), brittle cornea syndrome (OMIM: 229200, 614170), spondylodysplastic (OMIM: 130070), musculocontractural (OMIM: 601776), myopathic (OMIM: 616471), and periodontal (OMIM: 130080)-has been linked to dominant and recessive variation in 19 genes with only hypermobile EDS having an unresolved genetic basis and considered a diagnosis of exclusion [10,14]. ...
Background
Heritable connective tissue disorders (HCTDs) consist of heterogeneous syndromes. The diagnosis of HCTDs is aided by genomic biotechnologies (e.g., next-generation sequencing panels) facilitating the discovery of novel variants causing disease.
Methods
Detailed clinical exam data and CLIA-approved genetic testing results from next generation sequencing of 74 genes known to play a role in HCTDs were manually reviewed and analyzed in one hundred consecutive, unrelated patients with phenotypic features indicative of a HCTD referred over a 3.5-year period (2016–2020) to a specialized academic genetics clinic. The prevalence of symptoms was evaluated in the context of genetic variants. We also determined if symptoms among different organ systems were related and performed latent class analysis to identify distinct groups of patients based on symptomatology.
Results
In the cohort of 100 consecutive, unrelated individuals there were four pathogenic, six likely pathogenic and 35 classified potentially pathogenic variants of unknown clinical significance. Patients with potentially pathogenic variants exhibited similar symptom profiles when compared to patients with pathogenic/likely pathogenic variants in the same genes. Although results did not meet a multiple testing corrected threshold, patients with connective tissue symptoms had suggestive evidence of increased odds of having skin (odds ratio 2.18, 95% confidence interval 1.12 to 4.24) and eye symptoms (odds ratio 1.89, 95% confidence interval 0.98 to 3.66) requiring further studies. The best performing latent class analysis results were identified when dividing the dataset into three distinct groups based on age, gender and presence or absence of symptoms in the skeletal, connective tissue, nervous, gastrointestinal and cardiovascular systems. These distinct classes of patients included individuals with: (1) minimal skeletal symptoms, (2) more skeletal but fewer connective tissue, nervous or gastrointestinal symptoms and (3) more nervous system symptoms.
Conclusions
We used novel approaches to characterize phenotype-genotype relationships, including pinpointing potentially pathogenic variants, and detecting unique symptom profiles in patients with features of HCTDs. This study may guide future diagnosis and disease/organ system monitoring with continued improvement and surveillance by clinicians for patients and their families.
... The genetic cause of hEDS is not clearly defined, but some cases were recently associated with dominant TNXB gene mutations, causing Tenascin X defects or haploinsufficiency [11,51]. Association of tenascin X with collagen network, other extracellular matrix components and involvement in extracellular matrix remodeling and maturation could largely explain tissue homeostasis disruption in the rare cases of hEDS [54][55][56]. ...
Mutation of just a single extracellular matrix protein, a receptor or enzyme involved in connective tissue metabolism is sufficient to cause systemic pathologies and failure of tissues that are subjected to strong mechanical stresses. Skin histological and computerized image analyses can provide a good qualitative and quantitative indication of these inherited connective tissue diseases. In this study, skin biopsies from young (10 to 25 years) and middle-aged patients (26 to 50 years) suffering from Ehlers-Danlos syndromes (EDS), Marfan syndrome (MS) or pseudoxanthoma elasticum (PXE) were studied after specific staining of both the collagen and elastic networks. Findings from the histomorphometric analyses conducted on skin sections of the patients with EDS, MS and PXE were compared to skin sections of healthy subjects from the same age groups. Our results show that both the collagen and the elastic networks were affected in all the studied pathological cases, but that the adverse changes to the elastic network in older patients were distinct from the physiological changes observed during aging process for healthy subjects. This degenerative process may be explained by an added phenomenon involving a general connective tissue proteolysis.
... Due to many clinical features that are common with other types of EDS (especially with the EDS classical type) and other non-inflammatory connective tissue disorders, proper recognition of this condition is difficult in many patients. Some reports point to the TNXB gene as an hEDS genetic factor [3,4]. However, the fact that mutations in TNXB were detected only in a small percentage of hEDS as well as their recessive inheritance patterns suggests that TNXB is not the main hEDS-related gene. ...
Introduction:
Hypermobile (hEDS) Ehlers-Danlos syndrome (EDS) is a non-inflammatory, autosomal dominant connective tissue disorder. hEDS, unlike other types of EDS, has no known genetic aetiology, so diagnosis is conducted based on a person's medical history, a physical examination, and exclusion of other types of EDS after genetic tests.
Aim:
The present study was a sequencing analysis of the SERPINH1 gene and the evaluation of the potential impact of variants of this gene on their role in the aetiology of the hypermobile type of EDS.
Material and methods:
The study group included 100 hEDS patients of Polish origin. The SERPINH1 gene analysis was performed on genomic DNA (gDNA). In all patients, other types of EDS or other connective tissue disorders were excluded by testing them with NGS technology.
Results:
Among 100 tested patients, 4 different types of missense variants (heterozygote) were detected. All SERPINH1 alterations were classified as benign according to ACMG guidelines.
Conclusions:
Mutations in the SERPINH1 gene have been described in a rare type of OI but have never been analysed in hypermobile Ehlers-Danlos syndrome. In our investigation among 100 hEDS patients, we did not identify pathogenic or likely pathogenic variants. Though only benign variants were detected, which play no role in the pathogenesis of hEDS, we should take into account mechanisms other than gene structure alterations, which may have an impact on collagen and other ECM protein transport.
... Ehlers-Danlos syndrome (EDS) is a connective tissue disorder comprised of several types due to mutations in genes encoding proteins (e.g., collagen) such as COL5A1 and COL5A2 accounting for 50% of patients with a clinical diagnosis of classic EDS [1] . Classic EDS is an autosomal dominant disorder identified in one in 20000 individuals with stretchable skin, delayed wound healing with poor scarring, joint hypermobility with subluxations or dislocations, pes planus, easy bruisability, hernias, aneurysms, and cardiac abnormalities [2][3][4] . Historically, EDS is grouped into six categories (classic, hypermobile, vascular, kyphoscoliosis, arthrochalasia and dermatosparaxis) with different genetic causes and inheritance patterns [4,5] . ...
... Classic EDS is an autosomal dominant disorder identified in one in 20000 individuals with stretchable skin, delayed wound healing with poor scarring, joint hypermobility with subluxations or dislocations, pes planus, easy bruisability, hernias, aneurysms, and cardiac abnormalities [2][3][4] . Historically, EDS is grouped into six categories (classic, hypermobile, vascular, kyphoscoliosis, arthrochalasia and dermatosparaxis) with different genetic causes and inheritance patterns [4,5] . In 2017, EDS was assigned into 13 heritable disorders that affects an estimated 10 million people worldwide. ...
Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders comprised of several types. Classic EDS is an autosomal dominant disorder with stretchable skin, delayed wound healing with poor scarring, joint hypermobility with subluxations or dislocations, easy bruisability, hernias, aneurysms and cardiac abnormalities. Advances in genomics technology using next-generation sequencing has led to the discovery of causative genes for connective tissue disorders, hereditary cardiomyopathies and cardiovascular diseases including several genes for connective tissue disorders. A 55 year-old male exhibited thin stretchable skin, atrophic scars, easy bruising, joint pain and dislocations requiring multiple knee surgeries and a Beighton hyperflexibility score of 6 out of 7. He was found to have a heterozygous missense COL5A1 gene variant involving exon 3 at nucleotide c:305T>A with an amino acid position change at p.lle102Asn consistent with classic EDS. He had a heart transplant at 43 years of age due to cardiac failure of unknown cause. This patient with classic EDS is brought to medical attention and should be of interest to cardiologists, heart transplant specialists and surgeons, particularly in individuals with unexplained cardiac failure and then diagnosed prior to surgical intervention to avoid poor wound healing, scarring and other tissue involvement (e.g., vascular anomalies, blood pressure instability, aneurysms) as components of EDS.
... 231 Some other point mutations in TNXB have also been suggested to cause hEDS or classiclike EDS (clEDS). [231][232][233] TNXB haploinsufficiency has been identified in patients with an autosomal dominant form of hEDS who did not have the easy bruising and skin hyperextensibility as seen in TNX deficient EDS. 234 Patients with TNX haploinsufficiency and point mutations have distinct abnormalities in elastic fibers and normal collagen appearance. ...
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.
... Among the basic symptoms of EDS are elastic skin, susceptibility to injuries and hypermobility of joints [1,10]. The skin of people with EDS in most types is very delicate and thin giving the impression of being translucent [1][2][3][10][11][12][13][14][15][16]. Wounds take a long time to heal, and in the case of 4 other types of EDS not previouslymentioned, the damage leaves atrophic scars [15]. ...
Introduction and objective
Ehlers Danlos Syndrome – Hypermobile Type (EDS-HT), in which the genetic basis could not be determined and mutations of collagen fibrillar proteins were excluded, is one of the most common types of EDS. It is a disease characterized by many symptoms of varying severity. The purpose of the study is to determine the most important diagnostic factors for EDS-HT based on current literature.
Material and Methods
Searching PubMed publication databases, Google Scholar and Science Direct, by using a combination of key words: hEDS diagnosis, hypermobile EDS, hypermobility.
Brief description of the state of knowledge
19 papers were selected for the literature review, among which 8 concern the adequacy of the Beighton result in the diagnosis of EDS-HT, and another 11 the quality of life of people with EDS-HT, as well as the assessment and diagnosis of other symptoms accompanying this disease.
Conclusions
In order to diagnose EDS-HT, one should be guided not only by the established standard, which is the Beighton score, but also by additional tests that would confirm
the diagnostic decision and reduce the risk of error. Extension of diagnostic tests with additional criteria, which are presented in the article, would make diagnoses more accurate and reduce the possibility of false diagnoses. This is very important from the perspective of implementing appropriate treatment and the mental comfort of the patient.
... The TNXB gene spans 68.2 kb and contains 44 exons. It produces TNX, an extracellular matrix protein, which is highly expressed in connective tissue (12,13). The lack of TNX protein caused by mutation in or deletion of the TNXB gene can cause clinical manifestations related to Ehlers-Danlos syndrome (EDS) (14,15). ...
Purpose
Defects in both CYP21A2 and TNXB genes can cause congenital adrenal hyperplasia combined with hypermobility type Ehlers-Danlos syndrome, which has recently been named CAH-X syndrome. The purpose of this study is to assess the prevalence of chimeric TNXA/TNXB gene and clinical symptoms in a Chinese cohort with 21-hydroxylase deficiency (21-OHD).
Methods
A total of 424 patients with 21-OHD who were genetically diagnosed were recruited for this study. Multiplex ligation dependent probe amplification and sequencing were used to identify the CAH-X genotype. Clinical features of joints, skin, and others systems were evaluated in 125 patients.
Results
Here, 94 of the 424 patients had a deletion on at least one allele of CYP21A2 and 59 of them harbored heterozygotic TNXA/TNXB chimera. Frequencies of CAH-X CH-1, CH-2, and CH-3 were 8.2%, 3.1%, and 2.6%, respectively. The incidences of clinical features of EDS were 71.0% and 26.6% in patients with chimeric TNXA/TNXB genes or without (p<0.001). There were statistically significant differences in manifestations among the articular (p<0.001 in generalized hypermobility) and dermatologic (p<0.001 in hyperextensible skin, p=0.015 in velvety skin and p=0.033 in poor wound healing). The prevalence of generalized hypermobility was more common in CAH-X CH-2 or CH-3 than CH-1 patients (60% vs 20%, P=0.028).
Conclusions
In summary, about 14% of patients with 21-OHD may have chimeric TNXA/TNXB gene mutations in our study and most of them showed EDS related clinical symptoms. The correlation between CAH-X genotypes and clinical features in connective tissue like joint or skin needs to be further investigated.
... Classical-like EDS (clEDS) patients typically have mutations in the TNXB gene, in an autosomal recessive (AR) manor. 1 The mutations seen in the TNXB gene are varied and their symptoms are usually more severe than seen in the hypermobile EDS (hEDS) subtype. 5 clEDS patients present with manifestations of skin issues and hypermobility, and this subtype can be challenging to differentiate from hEDS. ...
An Osteopathic Family Physician will encounter hypermobile patients. Hypermobility is a symptom of many of the subtypes of the Ehlers Danlos Syndromes (EDS). With the updated classification system (the 2017 International Classification of the Ehlers-Danlos Syndromes) it is important for the osteopathic family physician to become familiar with the EDS patient. The classification system identifies 13 subtypes of EDS.1 Of these 13, 12 have a recognized genetic basis. Hypermobile EDS (hEDS) has a clinical diagnosis criteria checklist (Figure 1, page 29). There is opportunity for the osteopathic family physician community to help diagnose and treat the EDS population. This article seeks to have the osteopathic family physician become familiar with the Ehlers-Danlos Syndrome, and provide an overview of all of the subtypes of EDS, including hEDS and discusses signs, symptoms, and risks associated with the syndrome.
... These variants are frameshift (7/15), stop codon (4/15), or splicing (2/15) and lead to the insertion of a premature stop codon with a presumed loss of expression of the protein. Two out of these 15 variants (2/15) are missense which have detrimental effects on the proper protein folding and stability [10,13]. Among the 15 variants, 11 are identified in single patients/families. ...
TNXB-related classical-like Ehlers-Danlos syndrome (TNXB-clEDS) is an ultrarare type of Ehlers-Danlos syndrome due to biallelic null variants in TNXB, encoding tenascin-X. Less than 30 individuals have been reported to date, mostly of Dutch origin and showing a phenotype resembling classical Ehlers-Danlos syndrome without atrophic scarring. TNXB-clEDS is likely underdiagnosed due to the complex structure of the TNXB locus, a fact that complicates diagnostic molecular testing. Here, we report two unrelated Italian women with TNXB-clEDS due to compound heterozygosity for null alleles in TNXB. Both presented soft and hyperextensible skin, generalized joint hypermobility and related musculoskeletal complications, and chronic constipation. In addition, individual 1 showed progressive finger contractures and shortened metatarsals, while individual 2 manifested recurrent subconjunctival hemorrhages and an event of spontaneous rupture of the brachial vein. Molecular testing found the two previously unreported c.8278C > T p.(Gln2760*) and the c.(2358 + 1_2359 − 1)_(2779 + 1_2780 − 1)del variants in Individual 1, and the novel c.1150dupG p.(Glu384Glyfs*57) and the recurrent c.11435_11524+30del variants in Individual 2. mRNA analysis confirmed that the c.(2358 + 1_2359 − 1)_(2779 + 1_2780 − 1)del variant causes a frameshift leading to a predicted truncated protein [p.(Thr787Glyfs*40)]. This study refines the phenotype recently delineated in association with biallelic null alleles in TNXB, and adds three novel variants to its mutational repertoire. Unusual digital anomalies seem confirmed as possibly peculiar of TNXB-clEDS, while vascular fragility could be more than a chance association also in this Ehlers-Danlos syndrome type.
